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Title:
MODULATION OF TIMP1 AND TIMP2 EXPRESSION
Document Type and Number:
WIPO Patent Application WO/2012/044620
Kind Code:
A2
Abstract:
Provided herein are compositions, methods and kits for modulating expression of target genes, particularly of tissue inhibitor of metalloproteinase 1 and of tissue inhibitor of metalloproteinase 2 (TIMP1 and TIMP2, respectively). The compositions, methods and kits may include nucleic acid molecules (for example, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA) or short hairpin RNA (shRNA)) that modulate a gene encoding TIMP1 and TIMP2, for example, the gene encoding human TIMP1 and TIMP2. The composition and methods disclosed herein may also be used in treating conditions and disorders associated with TIMP1 and TIMP2 including fibrotic diseases and disorders including liver fibrosis, pulmonary fibrosis, peritoneal fibrosis and kidney fibrosis.

Inventors:
NIITSU YOSHIRO (JP)
TAKAHASHI HIROKAZU (JP)
TANAKA YASUNOBU (JP)
FEINSTEIN ELENA (IL)
AVKIN-NACHUM SHARON (IL)
KALINSKI HAGAR (IL)
METT IGOR (IL)
Application Number:
PCT/US2011/053496
Publication Date:
April 05, 2012
Filing Date:
September 27, 2011
Export Citation:
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Assignee:
NITTO DENKO CORP (JP)
QUARK PHARMACEUTICALS INC (US)
NIITSU YOSHIRO (JP)
TAKAHASHI HIROKAZU (JP)
TANAKA YASUNOBU (JP)
FEINSTEIN ELENA (IL)
AVKIN-NACHUM SHARON (IL)
KALINSKI HAGAR (IL)
METT IGOR (IL)
International Classes:
A61K48/00
Foreign References:
US20080113351A12008-05-15
Other References:
See references of EP 2621502A4
Attorney, Agent or Firm:
WHITTAKER, Michael, A. et al. (P.C.12707 High Bluff Drive, Suite 20, San Diego CA, US)
Download PDF:
Claims:
CLAIMS

That which is claimed is:

1. A nucleic acid molecule, wherein:

(a) the nucleic acid molecule includes a sense strand and an antisense strand;

(b) each strand of the nucleic acid molecule is independently 15 to 49 nucleotides in length;

(c) a 15 to 49 nucleotide sequence of the antisense strand is complementary to a sequence of an mR A encoding TIMP1; and

(d) a 15 to 49 nucleotide sequence of the sense strand is complementary to the antisense strand thereby generating a duplex region and includes a 15 to 49 nucleotide sequence of an mRNA encoding TIMP1 (SEQ ID NO: l).

2. The nucleic acid molecule of claim 1 wherein the antisense strand and the sense strand is selected from the sequence pairs set forth in siTIMPl_p2 (SEQ ID NOS:267 and 299); siTIMPl_p6 (SEQ ID NOS:268 and 300); siTIMPl_pl4 (SEQ ID NOS:269 and 301); siTIMPl_pl6 (SEQ ID NOS:270 and 302); siTIMPl_pl7 (SEQ ID NOS:271 and 303); siTIMPl_pl9 (SEQ ID NOS:272 and 304); siTIMPl_p20 (SEQ ID NOS:273 and 305); siTIMPl_p21 (SEQ ID NOS:274 and 306); siTIMPl_p23 (SEQ ID NOS:275 and 307;

siTIMPl_p29 (278 and 310); siTIMPl_p33 (280 and 312); siTIMPl_p38 (SEQ ID NOS:281 and 313); siTIMPl_p42 (282 and 314); siTIMPl_p43 (SEQ ID NOS:283 and 315);

siTIMPl_p45 (284 and 316); siTIMPl_p60 (SEQ ID NOS:286 and 318); siTIMPl_p71 (SEQ ID NOS:287 and 319); siTIMPl_p73 (SEQ ID NOS:288 and 320); siTIMPl_p78 (290 and 322); siTIMPl_p79 (SEQ ID NOS:291 and 323); siTIMPl_p85 (SEQ ID NOS:292 and 324); siTIMPl_p89 (SEQ ID NOS:293 and 325); siTIMPl_p91 (SEQ ID NOS:294 and 326); siTIMPl_p96 (SEQ ID NOS:295 and 327); siTIMPl_p98 (SEQ ID NOS:296 and 328); siTIMPl_p99 (SEQ ID NOS:297 and 329) and siTIMPl_pl08 (SEQ ID NOS:298 and 330).

3. The nucleic acid molecule of claim 1, wherein the sense strand and antisense strand are selected from the sequence pairs shown in Table C set forth as TIMP1-A (SEQ ID NOS:5 and 6); TIMP1-B (SEQ ID NOS:7 and 8) and TIMPl-C (SEQ ID NO:9 and 10).

4. The nucleic acid molecule of claim 1, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 comprises a sequence complimentary to a sequence between nucleotides 300-400 of SEQ ID NO: 1.

5. The nucleic acid molecule of claim 1, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 comprises a sequence complimentary to a sequence between nucleotides 600-750 of SEQ ID NO: 1.

6. The nucleic acid molecule of claim 4, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 comprises a sequence complimentary to a sequence between nucleotides 355-373 of SEQ ID NO: 1.

7. The nucleic acid molecule of claim 5, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 comprises a sequence complimentary to a sequence between nucleotides 620-638 or 640-658 of SEQ ID NO: 1.

8. A nucleic acid molecule, wherein:

(a) the nucleic acid molecule includes a sense strand and an antisense strand;

(b) each strand of the nucleic acid molecule is independently 15 to 49 nucleotides in length;

(c) a 15 to 49 nucleotide sequence of the antisense strand is complementary to a sequence of an mRNA encoding TIMP2; and

(d) a 15 to 49 nucleotide sequence of the sense strand is complementary to the antisense strand thereby generating a duplex region and includes a 15 to 49 nucleotide sequence of an mRNA encoding TIMP2 (SEQ ID NO:2).

9. The nucleic acid molecule of claim 8, wherein the sense strand and antisense strand are selected from the sequence pairs shown in Table D.

10. The nucleic acid molecule of claim 8, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 698-716 of SEQ ID NO: 2.

11. The nucleic acid molecule of claim 8, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 400-500 of SEQ ID NO: 2.

12. The nucleic acid molecule of claim 8, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 500-600 of SEQ ID NO: 2.

13. The nucleic acid molecule of claim 8, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 600-700 of SEQ ID NO: 2.

14. The nucleic acid molecule of claim 10, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 421-439 of SEQ ID NO: 2.

15. The nucleic acid molecule of claim 11, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 502-520 or 523-541 of SEQ ID NO: 2.

16. The nucleic acid molecule of claim 12, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 625-643 of SEQ ID NO: 2.

17. The nucleic acid molecule of claim 12, wherein said sequence of said antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 comprises a sequence complimentary to a sequence between nucleotides 629-647 of SEQ ID NO:2.

18. The nucleic acid molecule of claims 1 or 8, wherein the antisense strand and the sense strand are independently 17 to 49 nucleotides in length.

19. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are independently 17-30 nucleotides in length.

20. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are independently 15-25 nucleotides in length.

21. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are independently 18-23 nucleotides in length.

22. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are independently 19-21 nucleotides in length.

23. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are independently 25-30 nucleotides in length.

24. The nucleic acid molecule of claim 18, wherein the antisense strand and the sense strand are each 19 nucleotides in length.

25. The nucleic acid molecule of claims 1 or 8, wherein the duplex region is 15-49 nucleotides in length.

26. The nucleic acid molecule of claim 25, wherein the duplex region is 15-35 nucleotides in length.

27. The nucleic acid molecule of claim 25, wherein the duplex region is 15-25 nucleotides in length.

28. The nucleic acid molecule of claim 25, wherein the duplex region is 17-23 nucleotides in length.

29. The nucleic acid molecule of claim 25, wherein the duplex region is 17-21 nucleotides in length.

30. The nucleic acid molecule of claim 25, wherein the duplex region is 25-30 nucleotides in length.

31. The nucleic acid molecule of claim 25, wherein the duplex region is 15-25 nucleotides in length.

32. The nucleic acid molecule of claim 25, wherein the duplex region is 19 nucleotides in length.

33. The nucleic acid molecule of claims 1 or 8, wherein said antisense and sense strands are separate polynucleotide strands.

34. The nucleic acid molecule of claim 33, wherein said antisense and sense strands are separate polynucleotide strands; and wherein said antisense and sense strands form a double stranded structure by hydrogen bonding.

35. The nucleic acid molecule of claim 33, wherein said antisense and sense strands are separate polynucleotide strands; and wherein said antisense and sense strands are linked by covalent bonding.

36. The nucleic acid molecule of any of claims 1 to 32, wherein the sense and antisense strands are part of a single polynucleotide strand having both a sense and antisense region.

37. The nucleic acid molecule of claim 36, wherein the sense and antisense strands are part of a single polynucleotide strand having both a sense and antisense region, and wherein the nucleic acid molecule has a hairpin structure.

38. The nucleic acid molecule of any of claims 1 to 32, wherein the nucleic acid molecule is a double stranded molecule and is blunt ended on both ends.

39. The nucleic acid molecule of any of claims 1 to 32, wherein the nucleic acid molecule is a double stranded molecule and is blunt ended on one end.

40. The nucleic acid molecule of any of claims 1 to 32, wherein the nucleic acid molecule is a double stranded molecule and has at least one overhang on both ends of the molecule.

41. The nucleic acid molecule of any of claims 1 to 32, wherein the nucleic acid molecule is a double stranded molecule wherein at least one strand has a 3' - nucleotide or nonucleotide overhang.

42. The nucleic acid molecule of claim 41, wherein the nucleic acid molecule is a double stranded molecule and has a 3 '-overhang on both ends of the molecule; wherein said overhangs are 2 nucleotides in length.

43. The nucleic acid molecule of claim 40, wherein the nucleic acid molecule is a double stranded molecule and has a 5 '-overhang on at least one end of the molecule.

44. The nucleic acid molecule of claim 43, wherein the nucleic acid molecule is a double stranded molecule and has a 5 '-overhang on both ends of the molecule; wherein said overhangs are 2 nucleotides in length.

45. The nucleic acid molecule of claim 39, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule.

46. The nucleic acid molecule of claim 45, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 1-8 nucleotide overhang.

47. The nucleic acid molecule of claim 45, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 3 ' nucleotide or non-nucleotide overhang.

48. The nucleic acid molecule of claim 47, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a two-nucleotide 3 '-overhang.

49. The nucleic acid molecule of claim 47, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 3 '-overhang; and wherein said overhang is on the sense strand.

50. The nucleic acid molecule of claim 47, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 3 '-overhang; and wherein said overhang is on the antisense strand.

51. The nucleic acid molecule of claim 46, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 5 '-overhang.

52. The nucleic acid molecule of claim 46, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a two-nucleotide 5 '-overhang.

53. The nucleic acid molecule of claim 46, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 5 '-overhang; and wherein said overhang is on the sense strand.

54. The nucleic acid molecule of claim 46, wherein the nucleic acid molecule is a double stranded molecule and has a blunt end on one end of the molecule and an overhang on the other end of the molecule; wherein said overhang is a 5 '-overhang; and wherein said overhang is on the antisense strand.

55. The nucleic acid molecule of claim 46, wherein overhang nucleotides are modified nucleotides.

56. The nucleic acid molecule of claim 55, wherein overhang nucleotides are 2'- deoxyribonucleotides .

57. The nucleic acid molecule of any of claims 1 to 56, wherein the nucleic acid molecule comprises one or more modifications or modified nucleotides.

58. The nucleic acid molecule of claim 57, wherein the nucleic acid molecule comprises one or more nucleotides comprising a modified sugar moiety.

59. The nucleic acid molecule of claim 58, wherein the nucleic acid molecule comprises one or more nucleotides comprising a modified sugar; and wherein said modified sugar moiety is independently selected from the group consisting of 2'-0-methyl, 2'- methoxyethoxy, 2'-deoxy, 2'-fluoro, 2'-allyl, 2'-0-[2-(methylamino)-2-oxoethyl], 4'-thio, 4'- (CH2)2 -0-2'-bridge, 2 '-locked nucleic acid, or 2'-0-(N-methylcarbamate).

60. The nucleic acid molecule of claim 57, wherein the nucleic acid molecule comprises one or more modified nucleobases.

61. The nucleic acid molecule of claim 60, wherein the nucleic acid molecule comprises one or more modified nucleobases; and wherein said one or more modified nucleobase are independently selected from the group consisting of xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5- trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, and acyclonucleotides.

62. The nucleic acid molecule of claim 57, wherein the nucleic acid molecule comprises one or more modifications to the phosphodiester backbone.

63. The nucleic acid molecule of claim 62, wherein the nucleic acid molecule comprises one or more modifications to the phosphodiester backbone; and wherein said one or more modifications to the phosphodiester backbone are independently selected from the group consisting of a phosphorothioate, 3 '-(or -5')deoxy-3'-(or -5')thio-phosphorothioate, phosphorodithioate, phosphoroselenates, 3 '-(or -5')deoxy phosphinates, borano phosphates, 3 '-(or -5')deoxy-3'-(or 5 '-)amino phosphoramidates, hydrogen phosphonates, borano phosphate esters, phosphoramidates, alkyl or aryl phosphonates and phosphotriester or phosphorus linkages.

64. The nucleic acid molecule of claim 57, wherein said nucleic acid molecule comprises one or more modifications in the sense strand but not the antisense strand.

65. The nucleic acid molecule of claim 57, wherein said nucleic acid molecule comprises one or more modifications in the antisense strand but not the sense strand.

66. The nucleic acid molecule of claim 57, wherein said nucleic acid molecule comprises one or more modifications in both the sense strand and the antisense strand.

67. The nucleic acid molecule of claim 57, wherein the sense strand includes a pattern of alternating modifications.

68. The nucleic acid molecule of claim 57, wherein the antisense strand includes a pattern of alternating modified and unmodified nucleotides.

69. The nucleic acid molecule of claim 67, wherein the sense strand includes a pattern of alternating modified and unmodified nucleotides, and wherein the modification is a 2'-0-methyl sugar moiety.

70. The nucleic acid molecule of claim 68, wherein the antisense strand includes a pattern of alternating modified and unmodified nucleotides, and wherein the modification is a 2'-0-methyl sugar moiety.

71. The nucleic acid molecule of claim 69, wherein the sense strand includes a pattern of alternating modified and unmodified nucleotides, wherein the modification is a 2'- O-methyl sugar moiety; and wherein the pattern starts with a modified nucleotide at the 5 ' end of the sense strand.

72. The nucleic acid molecule of claim 70, wherein the antisense strand includes a pattern of alternating modified and unmodified nucleotides, wherein the modification is a 2'- O-methyl sugar moiety; and wherein the pattern starts with a modified nucleotide at the 5 ' end of the antisense strand.

73. The nucleic acid molecule of claim 69, wherein the sense strand includes a pattern of alternating modified and unmodified nucleotides, wherein the modification is a 2'- O-methyl sugar moiety; and wherein the pattern starts with a modified nucleotide at the 3 ' end of the sense strand.

74. The nucleic acid molecule of claim 70, wherein the antisense strand includes a pattern of alternating modified and unmodified nucleotides, wherein the modification is a 2'- O-methyl sugar moiety; and wherein the pattern starts with a modified nucleotide at the 3 ' end of the antisense strand.

75. The nucleic acid molecule of claim 66, wherein both the sense and antisense strand include a pattern of alternating modified and unmodified nucleotides; wherein the modification is a 2'-0-methyl sugar moiety; and wherein the pattern is configured such that such that modified nucleotides of the sense strand are opposite unmodified nucleotides in the antisense strand and vice-versa.

76. The nucleic acid molecule of claim 66, wherein both the sense and antisense strand include a pattern of alternating modified and unmodified nucleotides; wherein the modification is a 2'-0-methyl sugar moiety; and wherein the pattern is configured such that such that each modified nucleotide of the sense strand is opposite a modified nucleotide in the antisense strand.

77. The nucleic acid molecule of any of the preceding claims, wherein one or both of the sense and/or antisense strands comprise 1-3 deoxyribonucleotides at the 3 '-end.

78. The nucleic acid molecule of any of the preceding claims, wherein one or both of the sense and/or antisense strands comprise a phosphate group at 5 '-end.

79. The nucleic acid molecule of any of the preceding claims, wherein the sense strand comprises at least one nick or gap.

80. A method of reducing the expression of TIMP1 in a cell, comprising introducing into a cell a nucleic acid molecule of any of claims 1 to 7 in an amount sufficient to reduce expression of TIMP1.

81. A method of reducing the expression of TIMP2 in a cell, comprising introducing into a cell a nucleic acid molecule of any of claims 8 to 17 in an amount sufficient to reduce expression of TIMP2.

82. The method of claim 80 or 81, wherein said cell is a hepatocellular stellate cell.

83. The method of claim 80 or 81, wherein said cell is a stellate cell in or from renal or pulmonary tissue.

84. The method of any of claims 80 to 83, wherein said method is performed in vitro.

85. The method of any of claims 80 to 83, wherein said method is performed in vivo.

86. A method for treating an individual suffering from a disease associated with TIMP1 comprising administering to said individual a nucleic acid molecule of any of claims 1-7 in an amount sufficient to reduce expression of TIMP1.

87. A method for treating an individual suffering from a disease associated with TIMP2 comprising administering to said individual a nucleic acid molecule of any of claims 8-17 in an amount sufficient to reduce expression of TIMP2.

88. The method of claim 86 or 87, wherein said disease associated with TIMP1 or TIMP2 is a disease selected from the group consisting of fibrosis, liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis.

89. A composition comprising a nucleic acid molecule of any of claims 1-79 and a pharmaceutically acceptable carrier.

90. A composition comprising a nucleic acid molecule of any of claims 1-79 packaged for use by a patient.

91. The composition of claim 89 or 90, wherein the composition includes a label or package insert that provides certain information about how said nucleic acid molecule of any of the preceding claims may be used.

92. The composition of claim 91, wherein said label or package insert includes dosing information and or indications for use.

93. The composition of claim 91 or 92, wherein said label or package insert includes indications for use.

94. The composition of any of claims 91-93, wherein said label or package insert indicates that said nucleic acid molecule of any of the preceding claims is suitable for use in therapy.

95. The composition of any of claims 91-94, wherein said label or package insert indicates that said nucleic acid molecule of any of the preceding claims is suitable for use in treating a patient suffering from a disease associated with TIMP1.

96. The composition of any of claims 91-94, wherein said label or package insert indicates that said nucleic acid molecule of any of the preceding claims is suitable for use in treating a patient suffering from a disease associated with TIMP2.

97. The composition of any of claims 91-96, wherein said label or package insert indicates that said nucleic acid molecule of any of the preceding claims is suitable for use in treating a patient suffering from a disease selected from the group consisting of fibrosis, liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, vocal cord fibrosis, intestinal fibrosis, fibrosis in the brain associated with cerebral infarction and fibrillogenesis.

98. A double stranded oligonucleotide compound having the structure (Al):

(Al) 5' (N)x - Z 3' (antisense strand)

3' Z'-(N')y -z" 5' (sense strand)

wherein each of N and N' is a ribonucleotide which may be unmodified or modified, or an unconventional moiety;

wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or

N' is joined to the next N or N' by a covalent bond;

wherein each of Z and Z' is independently present or absent, but if present is

independently 1-5 consecutive nucleotides or unconventional moieties or a combination thereof covalently attached at the 3 ' terminus of the strand in which it is present.

wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y;

each of x and y is independently an integer from 18 to 40; wherein the sequence of (N')y has complementarity to the sequence of (N)x; and wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO: l or SEQ ID NO:2.

99. The nucleic acid molecule of claim 98 wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO: 1 and wherein (N)x comprises an antisense oligonucleotide present in any one of Tables Al, A2, A3 or A4.

100. The nucleic acid molecule of claim 99 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables A3 or A4.

101. The nucleic acid molecule of claim 98 wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:2.

102. The nucleic acid molecule of claim 101 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables Bl, B2, B3 or B4.

103. The nucleic acid molecule of claim 102 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables B3 or B4.

104. The nucleic acid molecule of claim 98, wherein none of the strands comprise a phosphate at the 3 ' and 5 ' termini or wherein one or both of the sense and/or antisense strands comprise a phosphate group at the 5 '-terminus.

105. The nucleic acid molecule of any of claims 98-104 wherein x = y =19.

106. The nucleic acid molecule of any of claims 98-105 wherein both Z and Z' are absent.

107. The nucleic acid molecule of any of claims 98-105 wherein one of Z or Z' is present.

108. The nucleic acid molecule of claim 107 wherein Z or Z' is independently an unconventional moiety selected from an abasic deoxyribose moiety, an abasic ribose moiety an inverted abasic deoxyribose moiety, an inverted abasic ribose moiety; a C3 moiety, a C4 moiety, a C5 moiety, a C6 moiety, and an amino-6 moiety.

109. The nucleic acid molecule of claim 108 wherein Z or Z' is independently selected from a C3 and an amino-C6 moiety.

110. The nucleic acid molecule of any of claims 98-109 wherein at least one of N or N' comprises a 2' sugar modified ribonucleotide.

111. The nucleic acid molecule of claim 110 wherein the 2' sugar modified ribonucleotide comprises the presence of an amino, a fluoro, an alkoxy or an alkyl moiety.

112. The nucleic acid molecule of any claim 111 wherein the 2' sugar modified ribonucleotide comprises 2'-OCH3 (2'OMe).

113. The nucleic acid molecule of claim 112 wherein (N)x comprises alternating 2'OMe sugar modified ribonucleotides and unmodified ribonucleotides.

114. The nucleic acid molecule of claim 113 wherein (N)x comprises at least 5 alternating 2'OMe sugar modified and unmodified ribonucleotides.

115. The nucleic acid molecule of claim 114 wherein (N)x comprises 2'OMe modified ribonucleotides at positions 2, 4, 6, 8, 11, 13, 15, 17 and 19.

116. The nucleic acid molecule of claim 114 wherein (N)x comprises 2'OMe modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19.

117. The nucleic acid molecule of claim 114 wherein (N)x comprises 2'OMe modified pyrimidines.

118. The nucleic acid molecule of any of claims 98-117 wherein (N')y comprises at least one unconventional moiety selected from a mirror nucleotide and a nucleotide joined to an adjacent nucleotide by a 2 '-5 ' internucleotide phosphate bond.

119. The nucleic acid molecule of claim 118 wherein the unconventional moiety is a mirror nucleotide.

120. The nucleic acid molecule of claim 119 wherein the mirror nucleotide is an L- deoxyribonucleotide (L-DNA).

121. The nucleic acid molecule of claim 120 wherein x=y =19; and wherein (N')y, consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3' penultimate position (position 18, 5'>3').

122. The nucleic acid molecule of claim 120 wherein x=y =19; and wherein (N')y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3' penultimate position (positions 17 and 18).

123. The nucleic acid molecule of claim 118 wherein the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2'-5' internucleotide phosphate linkage.

124. The nucleic acid molecule of claim 123 wherein the nucleotide joined to an adjacent nucleotide by a 2'-5' internucleotide phosphate linkage further comprises a 3'-0- methyl (3'OMe) sugar modification.

125. A double stranded nucleic acid molecule having a structure (A2) set forth below:

(A2) 5' Nl-(N)x - Z 3' (antisense strand)

3' Z'-N2-(N')y 5 ' (sense strand)

wherein each of N2, N and N' is independently an unmodified or modified

ribonucleotide, or an unconventional moiety;

wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or

N' is joined to the adjacent N or N' by a covalent bond;

wherein each of x and y is independently an integer from 17 to 39;

wherein the sequence of (N')y has complementarity to the sequence of (N)x and (N)x has complementarity to a consecutive sequence in the mRNA set forth in SEQ

ID NO: l or SEQ ID NO:2;

wherein Nl is covalently bound to (N)x and is mismatched to the mRNA set forth in

SEQ ID NO: l or SEQ ID NO:2;

wherein Nl is a moiety selected from the group consisting of ribouridine, modified ribouridine deoxyribouridine, modified deoxyribouridine, riboadenine, modified riboadenine deoxyriboadenine, and modified deoxyriboadenine; and wherein each of Z and Z' is independently present or absent, but if present is

independently 1-5 consecutive nucleotides or unconventional moieties or a combination thereof covalently attached at the 3 ' terminus of the strand in which it is present.

126. The nucleic acid molecule of claim 125 wherein x =y=18.

127. The nucleic acid molecule of claim 125 or 126 wherein (N)x comprises an antisense sequence to an mR A set forth in SEQ ID NO: 1.

128. The nucleic acid molecule of claim 127 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables A5, A6, A7 or A8.

129. The nucleic acid molecule of claim 128 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables A7 or A8.

130. The nucleic acid molecule of claim 125 or 126 wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:2.

131. The nucleic acid molecule of claim 130 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables B5, B6, B7 or B8.

132. The nucleic acid molecule of claim 131 wherein (N)x comprises an antisense oligonucleotide present in any one of Tables B7 or B8.

133. A nucleic acid molecule consisting of four ribonucleotide strands forming three siRNA duplexes having the general structure:

wherein each of oligo A, oligo B, oligo C, oligo D, oligo E and oligo F represents at least 19 consecutive ribonucleotides, wherein from 19 to 40 of such consecutive ribonucleotides, in each of oligo A, B, C, D, E and F comprise a strand of a siR A duplex, wherein each ribonucleotide may be modified or unmodified;

wherein strand 1 comprises oligo A which is either a sense portion or an antisense portion of a first siRNA duplex of the nucleic acid molecule, strand 2 comprises oligo B which is complementary to at least 19 nucleotides in oligo A, and oligo A and oligo B together form a first siRNA duplex that targets a first target mRNA;

wherein strand 1 further comprises oligo C which is either a sense portion or an

antisense strand portion of a second siRNA duplex of the nucleic acid molecule, strand 3 comprises oligo D which is complementary to at least 19 nucleotides in oligo C and oligo C and oligo D together form a second siRNA duplex that targets a second target mRNA;

wherein strand 4 comprises oligo E which is either a sense portion or an antisense strand portion of a third siRNA duplex of the nucleic acid molecule, strand 2 further comprises oligo F which is complementary to at least 19 nucleotides in oligo E and oligo E and oligo F together form a third siRNA duplex that targets a third target mRNA;

wherein linker A is a moiety that covalently links oligo A and oligo C; linker B is a moiety that covalently links oligo B and oligo F, and linker A and linker B can be the same or different; and wherein the nucleic acid molecule includes at least one antisense strand and sense strand pair set forth in any one of Tables A-B.

134. A pharmaceutical composition comprising a nucleic acid molecule of any of claims 1 to 133 and a pharmaceutically acceptable carrier.

135. A method of treating a subject suffering from a disease or condition selected from an organ specific fibrotic affecting any one or more of the brain, Skin, Peritoneum, Liver, Kidney, Heart, Lung, Bone marrow, Eye, Vasculature, intestine, vocal cord comprising administering to the subject nucleic acid molecule of any of claims 1-133 in an amount effective to treat the disease or condition.

136. A method of treating a subject suffering from a disease or condition selected from an organ specific fibrotic affecting any one or more of the Skin, Peritoneum, Liver, Kidney, Heart, Lung, Bone marrow, Eye, Vasculature, brain, vocal cord, intestine comprising administering to the subject nucleic acid molecule of any of claims 1 to 133 in an amount effective to treat the disease or condition.

137. The method of claim 136 wherein the disease or condition selected from a fibrotic condition such as liver fibrosis; kidney fibrosis for any reason (CKD including ESRD); lung fibrosis (including ILF); myelofibrosis, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma; cardiofibrosis, fibrosis associated with brain infarction, failure of glaucoma filtering operation; intestinal adhesions.

138. A composition comprising a nucleic acid molecule of any of claims 1 to 133 packaged for use by a patient.

139. The composition of claim 138 wherein the composition includes a label or package insert that provides certain information about how said nucleic acid molecule of any of claims 1 to 133 may be used.

140. The composition of claim 139 wherein said label or package insert includes dosing information.

141. The composition of claim 139 wherein said label or package insert includes indications for use.

142. The composition of claim 139, wherein said label or package insert indicates that said nucleic acid molecule of any of claims 1 to 133 is suitable for use in therapy.

143. The composition of claim 142 wherein said label or package insert indicates that said nucleic acid molecule of any of claims 1 to 133 is suitable for use in treating a patient suffering from a disease associated with TIMP1.

144. The composition of claim 142 wherein said label or package insert indicates that said nucleic acid molecule of any of 1 to 133 is suitable for use in treating a patient suffering from a disease associated with TIMP2.

145. The composition of claim 143 or 144, wherein said label or package insert indicates that said nucleic acid molecule of any of claims 1 to 133 is suitable for use in treating a patient suffering from a disease selected from the group consisting of fibrosis, liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis.

Description:
MODULATION OF TIMP1 AND TIMP2 EXPRESSION

RELATED PATENT APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Application Serial No. 61/388,572 filed September 30, 2010 entitled "Modulation of TIMP1 and TIMP2 Expression" and which is incorporated herein by reference in its entirety and for all purposes.

SEQUENCE LISTING

[002] The instant application contains a Sequence Listing which is entitled 224-PCTl_ST25.txt, said ASCII copy, created on August 24, 2011 and is 910 kb in size, is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[003] Provided herein are compositions and methods for modulating expression of TIMP1 and TIMP2.

BACKGROUND OF THE INVENTION

[004] Sato, Y., et al. disclose the administration of vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homo log of human heat shock protein 47, to liver cirrhosis rat animal models. Sato, Y., et al, Nature Biotechnology, vol. 26(4), p. 431-442 (2008).

[005] Chen, J-J., et al. disclose transfecting human keloid samples with HSP-47-shRNA (small hairpin RNA) to examine proliferation of keloid fibroblast cells. Chen, J-J., et al., British Journal of Dermatology, vol. 156, p. 1188-1195 (2007).

[006] PCT Patent Publication No. WO 2006/068232 discloses an astrocyte specific drug carrier which includes a retinoid derivative and/or a vitamin A analog.

[007] PCT Patent Publication Nos. WO 2008/104978 and WO 2007/091269 disclose siRNA structures and compounds. [008] PCT Patent Publication No. WO 2011/072082 discloses double stranded RNA compounds targeting HSP47 (SERPINH1).

SUMMARY OF THE INVENTION

[009] Compositions, methods and kits for modulating expression of target genes are provided herein. In various aspects and embodiments, compositions, methods and kits provided herein modulate expression of tissue inhibitor of metalloproteinases 1 and tissue inhibitor of metalloproteinases 2 also known as TIMP1 and TIMP2, respectively. The compositions, methods and kits may involve use of nucleic acid molecules (for example, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA) or short hairpin RNA (shRNA)) that bind a nucleotide sequence (such as an mRNA sequence) encoding TIMP1 and TIMP2, for example, the mRNA coding sequence for human TIMP1 exemplified by SEQ ID NO: l and the mRNA coding sequence for human TIMP2 exemplified by SEQ ID NO:2. In certain preferred embodiments, the compositions, methods and kits disclosed herein inhibit expression of TIMP1 or TIMP2. For example, siNA molecules (e.g., RISC length dsNA molecules or Dicer length dsNA molecules) are provided that down regulate, reduce or inhibit TIMP1 or TIMP2 expression. Also provided are compositions, methods and kits for treating and/or preventing diseases, conditions or disorders associated with TIMP1 and TIMP2, including organ specific fibrosis associated with at least one of brain, skin fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis, vascular fibrosis, bone marrow fibrosis, eye fibrosis, intestinal fibrosis, vocal cord fibrosis or other fibrosis. Specific indications include liver fibrosis, cirrhosis, pulmonary fibrosis including Interstitial lung fibrosis (ILF), kidney fibrosis resulting from any condition (e.g., CKD including ESRD), peritoneal fibrosis, chronic hepatic damage, fibrillogenesis, fibrotic diseases in other organs, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic

(operations); scleroderma; cardiofibrosis, failure of glaucoma filtering operation; brain fibrosis associated with cerebral infarction; and intestinal adhesions and Crohn's disease. The compounds are useful in treating organ specific indications including those shown in Table I infra.

[0010] In one aspect, provided are nucleic acid molecules (e.g., siNA molecules) in which (a) the nucleic acid molecule includes a sense strand (passenger strand) and an antisense strand (guide strand); (b) each strand of the nucleic acid molecule is independently 15 to 49 nucleotides in length; (c) a 15 to 49 nucleotide sequence of the antisense strand is complementary to a sequence of an mRNA encoding a human TIMP (e.g., SEQ ID NO: 1 or SEQ ID NO:2); and (d) a 15 to 49 nucleotide sequence of the sense strand is complementary to the sequence of the antisense strand and includes a 15 to 49 nucleotide sequence of an mRNA encoding human TIMP1 or TIMP2 (e.g., SEQ ID NO: 1 or SEQ ID NO:2, respectively). In various embodiments the sense and antisense strands generate a 15 to 49 base pair duplex.

[0011] In certain embodiments, the sequence of the antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 includes a sequence complimentary to a sequence between nucleotides 193-813 or 1-192; or 813-893 of SEQ ID NO: 1; or between nucleotides 1-200; or 800-893 of SEQ ID NO: 1.

[0012] In certain embodiments the sequence of the antisense comprises an antisense sequence set forth in any one of Tables A1-A8 or C. In preferred embodiments the sequence of the antisense comprises an antisense sequence set forth in Tables A3, A4, A7, A8, or C. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table A3 or Table A4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table A7 or Table A8. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table C.

[0013] In certain embodiments, the sequence of the antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 includes a sequence complimentary to a sequence between nucleotides 303-962 or 1-303; or 962-3369; of SEQ ID NO: 2; or between nucleotides 1-350; or 950-3369 of SEQ ID NO: 2.

[0014] In certain embodiments the sequence of the antisense comprises an antisense sequence set forth in any one of Tables B1-B8 or D. In preferred embodiments the sequence of the antisense comprises an antisense sequence set forth in Tables B3, B4, B7, B8, D. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table B3 or Table B4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table B7 or Table B8. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table D. [0015] In some embodiments, the antisense strand includes a sequence that is complementary to a sequence of an mR A encoding human TIMP1 corresponding to nucleotides 355-373 of SEQ ID NO: 1 or a portion thereof; or nucleotides 620-638 of SEQ ID NO: 1 or a portion thereof; or nucleotides 640-658 of SEQ ID NO: 1 or a portion thereof.

[0016] In some embodiments, the antisense strand includes a sequence that is

complementary to a sequence of an mRNA encoding human TIMP2 corresponding to nucleotides 421-439 of SEQ ID NO: 2 or a portion thereof; or nucleotides 502-520 of SEQ ID NO: 2 or a portion thereof; or nucleotides 523-541 of SEQ ID NO: 2 or a portion thereof; or nucleotides 625-643 of SEQ ID NO: 2 or a portion thereof; or nucleotides 629-647 of SEQ ID NO: 2 or a portion thereof

[0017] In some embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown in Table Al or A5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table Al . In certain preferred embodiments the antisense strand and the sense strand are selected from the sequence pairs shown in Table A5. In some preferred embodiments the antisense and sense strands are selected from the sequence pairs shown in Table A3 or Table A7.

[0018] In certain embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown in Table C.

[0019] In various embodiments of nucleic acid molecules (e.g., siNA molecules) as disclosed herein, the antisense strand may be 15 to 49 nucleotides in length (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); or 17-35 nucleotides in length; or 17- 30 nucleotides in length; or 15-25 nucleotides in length; or 18-25 nucleotides in length; or 18-23 nucleotides in length; or 19-21 nucleotides in length; or 25-30 nucleotides in length; or 26-28 nucleotides in length. Similarly the sense strand of nucleic acid molecules (e.g., siNA molecules) as disclosed herein may be 15 to 49 nucleotides in length (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); or 17-35 nucleotides in length; or 17- 30 nucleotides in length; or 15-25 nucleotides in length; or 18-25 nucleotides in length; or 18-23 nucleotides in length; or 19-21 nucleotides in length; or 25-30 nucleotides in length; or 26-28 nucleotides in length. The duplex region of the nucleic acid molecules (e.g., siNA molecules) as disclosed herein may be 15-49 nucleotides in length (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); 18-40 nucleotides in length; or 15-35 nucleotides in length; or 15-30 nucleotides in length; or about 15-25 nucleotides in length; or 17-25 nucleotides in length; or 17-23 nucleotides in length; or 17-21 nucleotides in length; or 19-21 nucleotides in length, or 25-30 nucleotides in length; or 25-28 nucleotides in length. In some embodiments the duplex region of the nucleic acid molecules (e.g., siNA molecules) is 19 nucleotides in length.

[0020] In certain embodiments, the sense and antisense strands of a nucleic acid (e.g., an siNA nucleic acid molecule) as provided herein are separate polynucleotide strands. In some embodiments, the separate antisense and sense strands form a double stranded structure via hydrogen bonding, for example, Watson-Crick base pairing. In some embodiments the sense and antisense strands are two separate strands that are covalently linked to each other. In other embodiments, the sense and antisense strands are part of a single polynucleotide strand having both a sense and antisense region; in some preferred embodiments the polynucleotide strand has a hairpin structure.

[0021] In certain embodiments, the nucleic acid molecule (e.g., siNA molecule) is a double stranded nucleic acid (dsNA) molecule that is symmetrical with regard to overhangs, and has a blunt end on both ends. In other embodiments the nucleic acid molecule (e.g., siNA molecule) is a dsNA molecule that is symmetrical with regard to overhangs, and has an overhang on both ends of the dsNA molecule; preferably the molecule has overhangs of 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides; preferably the molecule has 2 nucleotide overhangs. In some embodiments the overhangs are 5' overhangs; in alternative embodiments the overhangs are 3' overhangs. In certain embodiments, the overhang nucleotides are modified with modifications as disclosed herein. In some embodiments the overhang nucleotides are 2 ' -deoxyribonucleotides .

[0022] In some embodiments the molecules comprise non-nucleotide overhangs at one or more of the 5' or 3' terminus of the sense and/or antisense strands. Such non-nucleotide overhangs include abasic ribo- and deoxyribo-nucleotide moieties, alkyl moieties including C3-C3 moieties and amino carbon chains.

[0023] In certain preferred embodiments, the nucleic acid molecule (e.g., siNA molecule) is a dsNA molecule that is asymmetrical with regard to overhangs, and has a blunt end on one end of the molecule and an overhang on the other end of the molecule. In certain embodiments the overhang is 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides; preferably the overhang is 2 nucleotides. In some preferred embodiments an asymmetrical dsNA molecule has a 3'- overhang (for example a two nucleotide 3 '-overhang) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule. In some preferred embodiments an asymmetrical dsNA molecule has a 5 '-overhang (for example a two nucleotide 5 '-overhang) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule. In other preferred embodiments an asymmetrical dsNA molecule has a 3 '-overhang (for example a two nucleotide 3 '-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In some preferred embodiments an asymmetrical dsNA molecule has a 5'- overhang (for example a two nucleotide 5 '-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In certain preferred embodiments, the overhangs are 2'-deoxyribonucleotides. Examples of siNA compounds having a terminal dTdT are found in Tables C and D, infra.

[0024] In some embodiments, the nucleic acid molecule (e.g., siNA molecule) has a hairpin structure (having the sense strand and antisense strand on one polynucleotide), with a loop structure on one end and a blunt end on the other end. In some embodiments, the nucleic acid molecule has a hairpin structure, with a loop structure on one end and an overhang end on the other end (for example a 1, 2, 3, 4, 5, 6, 7, or 8 nucleotide overhang); in certain embodiments, the overhang is a 3 '-overhang; in certain embodiments the overhang is a 5'- overhang; in certain embodiments the overhang is on the sense strand; in certain

embodiments the overhang is on the antisense strand.

[0025] The nucleic acid molecules (e.g., siNA molecule) disclosed herein may include one or more modifications or modified nucleotides such as described herein. For example, a nucleic acid molecule (e.g., siNA molecule) as provided herein may include a modified nucleotide having a modified sugar; a modified nucleotide having a modified nucleobase; or a modified nucleotide having a modified phosphate group. Similarly, a nucleic acid molecule (e.g., siNA molecule) as provided herein may include a modified phosphodiester backbone and/or may include a modified terminal phosphate group.

[0026] Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more nucleotides that include a modified sugar moiety, for example as described herein. In some preferred embodiments the modified sugar moiety is selected from the group consisting of 2'-0-methyl, 2'-methoxyethoxy, 2'-deoxy, 2'-fluoro, 2'-allyl, 2'-0-[2-(methylamino)-2- oxoethyl], 4'-thio, 4'-(CH 2 ) 2 -0-2'-bridge, 2 '-locked nucleic acid, and 2'-0-(N- methylcarbamate) .

[0027] Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more modified nucleobase(s) for example as described herein, which preferably may be one selected from the group consisting of xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5- substituted uracils and cytosines, 7-methylguanine, and acyclonucleotides.

[0028] Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more modifications to the phosphodiester backbone, for example as described herein. In some preferred embodiments the phosphodiester bond is modified by substituting the

phosphodiester bond with a phosphorothioate, 3 '-(or -5')deoxy-3 '-(or -5')thio- phosphorothioate, phosphorodithioate, phosphoroselenates, 3 '-(or -5')deoxy phosphinates, borano phosphates, 3 '-(or -5')deoxy-3'-(or 5'-) amino phosphoramidates, hydrogen phosphonates, borano phosphate esters, phosphoramidates, alkyl or aryl phosphonates and phosphotriester or phosphorus linkages.

[0029] In various embodiments, the provided nucleic acid molecules (e.g., siNA molecules) may include one or modifications in the sense strand but not the antisense strand; in other embodiments the provided nucleic acid molecules (e.g., siNA molecules) include one or more modifications in the antisense strand but not the sense strand; in yet other embodiments, the provided nucleic acid molecules (e.g., siNA molecules) include one or more modifications in the both the sense strand and the antisense strand.

[0030] In some embodiments in which the provided nucleic acid molecules (e.g., siNA molecules) have modifications, the sense strand includes a pattern of alternating modified and unmodified nucleotides, and/or the antisense strand includes a pattern of alternating modified and unmodified nucleotides; in some preferred versions of such embodiments the modification is a 2'-0-methyl (2' methoxy or 2'OMe) sugar moiety. The pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5' end or 3' end of one of the strands; for example the pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5 ' end or 3 ' end of the sense strand and/or the pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5' end or 3' end of the antisense strand. When both the antisense and sense strand include a pattern of alternating modified nucleotides, the pattern of modified nucleotides may be configured such that modified nucleotides in the sense strand are opposite modified nucleotides in the antisense strand; or there may be a phase shift in the pattern such that modified nucleotides of the sense strand are opposite unmodified nucleotides in the antisense strand and vice-versa.

[0031] The nucleic acid molecules (e.g., siNA molecules) as provided herein may include 1- 3 (i.e., 1, 2 or 3) deoxyribonucleotides at the 3' end of the sense and/or the antisense strand.

[0032] The nucleic acid molecules (e.g., siNA molecules) as provided herein may include a phosphate group at the 5' end of the sense and/or the antisense strand.

[0033] In one aspect, provided are double stranded nucleic acid molecules having the structure (Al):

(Al) 5' (N)x - Z 3' (antisense strand)

3 ' Z'-(N')y -z" 5 ' (sense strand) wherein each of N and N' is a nucleotide which may be unmodified or modified, or an unconventional moiety; wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or N' is joined to the next N or N' by a covalent bond;wherein each of Z and Z' is independently present or absent, but if present independently includes 1-5 consecutive nucleotides or non- nucleotide moieties or a combination thereof covalently attached at the 3 ' terminus of the strand in which it is present;

wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y; each of x and y is independently an integer from 18 to 40; wherein the sequence of (N')y has complementarity to the sequence of (N)x; and wherein (N)x includes an antisense sequence to SEQ ID NO: l or to SEQ ID NO:2.

[0034] In some embodiments (N)x includes an antisense sequence to SEQ ID NO: l . In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables Al, A2, A3 or A4. In other embodiments (N)x is selected from an antisense oligonucleotide present in Tables A3 or A4.

[0035] In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table Al . In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A2. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table A2. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A3, and preferably in Table A4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in duplexes siTIMPl_p2; siTIMPl_p6; siTIMPl_pl4; siTIMPl_pl6; siTIMPl_pl7;

siTIMPl_pl9; siTIMPl_p20; siTIMPl_p21; siTIMPl_p23; siTIMPl_p24; siTIMPl_p27; siTIMPl_p29; siTIMPl_p31; siTIMPl_p33; siTIMPl_p38; siTIMPl_p42; siTIMPl_p43; siTIMPl_p45; siTIMPl_p49; siTIMPl_p60; siTIMPl_p71; siTIMPl_p73; siTIMPl_p77; siTIMPl_p78; siTIMPl_p79; siTIMPl_p85; siTIMPl_p89; siTIMPl_p91; siTIMPl_p96; siTIMPl_p98; siTIMPl_p99 and siTIMPl_pl08, shown in Table A3 infra. [0036] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMPl_p2 (SEQ ID NOS:267 and 299); siTIMPl_p6 (SEQ ID NOS:268 and 300); siTIMPl_pl4 (SEQ ID NOS:269 and 301); siTIMPl_pl6 (SEQ ID NOS:270 and 302); siTIMPl_pl7 (SEQ ID NOS:271 and 303); siTIMPl_pl9 (SEQ ID NOS:272 and 304); siTIMPl_p20 (SEQ ID NOS:273 and 305); siTIMPl_p21 (SEQ ID NOS:274 and 306); siTIMPl_p23 (SEQ ID NOS:275 and 307; siTIMPl_p29 (278 and 310);

siTIMPl_p33 (280 and 312); siTIMPl_p38 (SEQ ID NOS:281 and 313); siTIMPl_p42 (282 and 314); siTIMPl_p43 (SEQ ID NOS:283 and 315); siTIMPl_p45 (284 and 316); siTIMPl_p60 (SEQ ID NOS:286 and 318); siTIMPl_p71 (SEQ ID NOS:287 and 319); siTIMPl_p73 (SEQ ID NOS:288 and 320); siTIMPl_p78 (290 and 322); siTIMPl_p79 (SEQ ID NOS:291 and 323); siTIMPl_p85 (SEQ ID NOS:292 and 324); siTIMPl_p89 (SEQ ID NOS:293 and 325); siTIMPl_p91 (SEQ ID NOS:294 and 326); siTIMPl_p96 (SEQ ID NOS:295 and 327); siTIMPl_p98 (SEQ ID NOS:296 and 328); siTIMPl_p99 (SEQ ID NOS:297 and 329) and siTIMPl_pl08 (SEQ ID NOS:298 and 330), shown in Table A4, infra.

[0037] In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p2 (SEQ ID NOS:267 and 299). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p6 (SEQ ID NOS:268 and 300). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl4 (SEQ ID NOS:269 and 301). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl6 (SEQ ID NOS:270 and 302). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl7 (SEQ ID NOS:271 and 303). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl9 (SEQ ID NOS:272 and 304). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p20 (SEQ ID NOS:273 and 305). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p21 (SEQ ID NOS:274 and 306). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p23 (SEQ ID NOS:275 and 307. In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p29 (278 and 310). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p33 (280 and 312). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p38 (SEQ ID NOS:281 and 313). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p42 (282 and 314). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p43 (SEQ ID NOS:283 and 315). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p45 (284 and 316). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p60 (SEQ ID NOS:286 and 318). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p71 (SEQ ID NOS:287 and 319). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p73 (SEQ ID NOS:288 and 320). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p78 (290 and 322). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p79 (SEQ ID NOS:291 and 323). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p85 (SEQ ID NOS:292 and 324). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p89 (SEQ ID NOS:293 and 325). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p91 (SEQ ID NOS:294 and 326). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p96 (SEQ ID NOS:295 and 327). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p98 (SEQ ID NOS:296 and 328). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p99 (SEQ ID NOS:297 and 329). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl08 (SEQ ID NOS:298 and 330), shown in Table A4.

[0038] In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p2 (SEQ ID NOS:267 and 299). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p6 (SEQ ID NOS:268 and 300). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl6 (SEQ ID NOS:270 and 302). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl7 (SEQ ID NOS:271 and 303). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl9 (SEQ ID NOS:272 and 304). I In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p20 (SEQ ID NOS:273 and 305). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p21 (SEQ ID NOS:274 and 306). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p38 (SEQ ID NOS:281 and 313).

[0039] In some embodiments (N)x includes an antisense sequence to SEQ ID NO:2. In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables Bl, B2, B3 or B4. In other embodiments (N)x is selected from an antisense oligonucleotide present in Tables B3 or B4.

[0040] In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table Bl . In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B2. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table B2. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B3, and preferably in Table B4.

[0041] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p4; siTIMP2_pl6; siTIMP2_pl7; siTIMP2_pl 8; siTIMP2_p20; siTIMP2_p24; siTIMP2_p25; siTIMP2_p27; siTIMP2_p29; siTIMP2_p30; siTIMP2_p33; siTIMP2_p35; siTIMP2_p37; siTIMP2_p38; siTIMP2_p39; siTIMP2_p40; siTIMP2_p41; siTIMP2_p44; siTIMP2_p46; siTIMP2_p51; siTIMP2_p55; siTIMP2_p61; siTIMP2_p62; siTIMP2_p64; siTIMP2_p65; siTIMP2_p67; siTIMP2_p68; siTIMP2_p69; siTIMP2_p71; siTIMP2_p75; siTIMP2_p76; siTIMP2_p78; siTIMP2_p79; siTIMP2_p82; siTIMP2_p83; siTIMP2_p84; siTIMP2_p85; siTIMP2_p86; siTIMP2_p87; siTIMP2_p88; siTIMP2_p89; siTIMP2_p90; siTIMP2_p91; siTIMP2_p92; siTIMP2_p93; siTIMP2_p94; siTIMP2_p95; siTIMP2_p96; siTIMP2_p97; siTIMP2_p98; siTIMP2_p99; siTIMP2_pl00; and siTIMP2_pl01 and siTIMP2_pl02, shown in Table B3, infra.

[0042] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p27 (SEQ ID NOS:2478 and 2531); siTIMP2_p29 (SEQ ID NOS:2479 and 2532); siTIMP2_p30 (SEQ ID NOS:2480 and 2533); siTIMP2_p39 (SEQ ID NOS:2485 and 2538); siTIMP2_p40 (SEQ ID NOS:2486 and 2539); siTIMP2_p41 (SEQ ID NOS 2487 and 2540 siTIMP2_p46 (SEQ ID NOS:2489 and 2542); siTIMP2_p55 (SEQ ID

NOS 2491 and 2544 siTIMP2_p62 (SEQ ID NOS:2493 and 2546); siTIMP2_p68 (SEQ ID

NOS 2497 and 2550 siTIMP2_p69 (SEQ ID NOS:2498 and 2551); siTIMP2_p71 (SEQ ID

NOS 2499 and 2552 siTIMP2_p76 (SEQ ID NOS:2501 and 2554); siTIMP2_p78 (SEQ ID

NOS 2502 and 2555 siTIMP2_p89 (SEQ ID NOS:2511 and 2564); siTIMP2_p91 (SEQ ID

NOS 2513 and 2566 siTIMP2_p93 (SEQ ID NOS:2515 and 2568); siTIMP2_p95 (SEQ ID

NOS 2517 and 2570 siTIMP2_p97 (SEQ ID NOS:2519 and 2572); siTIMP2_p98 (SEQ ID

NOS 2520 and 2573 and siTIMP2_pl00 (SEQ ID NOS:2522 and 2575), shown in Table

B4, infra.

[0043] In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p27 (SEQ ID NOS:2478 and 2531). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p29 (SEQ ID NOS:2479 and 2532). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p30 (SEQ ID NOS:2480 and 2533). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p39 (SEQ ID NOS:2485 and 2538). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p40 (SEQ ID NOS:2486 and 2539). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p41 (SEQ ID NOS:2487 and 2540). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p46 (SEQ ID NOS:2489 and 2542). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p55 (SEQ ID NOS:2491 and 2544). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p62 (SEQ ID NOS:2493 and 2546). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p68 (SEQ ID NOS:2497 and 2550). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p69 (SEQ ID NOS:2498 and 2551). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p71 (SEQ ID NOS:2499 and 2552). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p76 (SEQ ID NOS:2501 and 2554). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p78 (SEQ ID NOS:2502 and 2555). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p89 (SEQ ID NOS:2511 and 2564). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p91 (SEQ ID NOS:2513 and 2566). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p93 (SEQ ID NOS:2515 and 2568). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p95 (SEQ ID NOS:2517 and 2570). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p97 (SEQ ID NOS:2519 and 2572). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p98 (SEQ ID NOS:2520 and 2573). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_pl00 (SEQ ID NOS:2522 and 2575). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_pl02 (SEQ ID NOS: 1007 and 1622).

[0044] In some embodiments the covalent bond joining each consecutive N or N' is a phosphodiester bond. [0045] In some embodiments x = y and each of x and y is 19, 20, 21, 22 or 23. In various embodiments x = y =19. In some embodiments the antisense and sense strands form a duplex by base pairing.

[0046] According to one embodiment provided are modified nucleic acid molecules having a structure (A2) set forth below:

(A2) 5' Nl-(N)x - Z 3' (antisense strand)

3' Z'-N2-(N')y -z" 5' (sense strand) wherein each of N2, N and N' is independently an unmodified or modified nucleotide, or an unconventional moiety; wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or N' is joined to the adjacent N or N' by a covalent bond;

wherein each of x and y is independently an integer of from 17 to 39; wherein the sequence of (N')y has complementarity to the sequence of (N)x and (N)x has complementarity to a consecutive sequence in a target mRNA selected from SEQ ID NO: 1 and SEQ ID NO:2; wherein Nl is covalently bound to (N)x and is mismatched to SEQ ID NO: 1 or to SEQ ID NO:2, wherein Nl is a moiety selected from the group consisting of uridine, modified uridine, ribothymidine, modified ribothymidine, deoxyribothymidine, modified

deoxyribothymidine, riboadenine, modified riboadenine, deoxyriboadenine or modified deoxyriboadenine; wherein Nl and N2 form a base pair; wherein each of Z and Z' is independently present or absent, but if present is independently 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3 ' terminus of the strand in which it is present; and wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y.

[0047] Molecules covered by the description of Structure A2 are also referred to herein as "18+1" or "18+1 mer". In some embodiments the N2-(N')y and Nl-(N)x oligonucleotide strands useful in generating dsRNA compounds are presented in Tables A5, A6, A7, A8, B5, B6, B7 or B8. In some embodiments (N)x has complementarity to a consecutive sequence in SEQ ID NO: 1 (human TIMP1 mRNA). In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables A5, A6, A7, and A8. In some embodiments x=y=18 and Nl-(N)x includes an antisense oligonucleotide present in any one of Tables A3 or A4. In some embodiments x=y=19 or x=y=20. In certain preferred embodiments x =y=18.

[0048] In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table A5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A6. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table A6. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A7, and preferably in Table A8.

[0049] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMPl_pl; siTIMPl_p3; siTIMPl_p4; siTIMPl_p5; siTIMPl_p7; siTIMPl_p8; siTIMPl_p9; siTIMPl_pl0; siTIMPl_pl l; siTIMPl_pl2; siTIMPl_pl3; siTIMPl_pl5; siTIMPl_pl8; siTIMPl_p22; siTIMPl_p25; siTIMPl_p26; siTIMPl_p28; siTIMPl_p30; siTIMPl_p32; siTIMPl_p34; siTIMPl_p35; siTIMPl_p36; siTIMPl_p37; siTIMPl_p39; siTIMPl_p40; siTIMPl_p41; siTIMPl_p44; siTIMPl_p46; siTIMPl_p47; siTIMPl_p48; siTIMPl_p50; siTIMPl_p51; siTIMPl_p52; siTIMPl_p53; siTIMPl_p54; siTIMPl_p55; siTIMPl_p56; siTIMPl_p57; siTIMPl_p58; siTIMPl_p59; siTIMPl_p61; siTIMPl_p62; siTIMPl_p63; siTIMPl_p64; siTIMPl_p65; siTIMPl_p66; siTIMPl_p67; siTIMPl_p68; siTIMPl_p69; siTIMPl_p70; siTIMPl_p72; siTIMPl_p74; siTIMPl_p75; siTIMPl_p76; siTIMPl_p80; siTIMPl_p81; siTIMPl_p82; siTIMPl_p83; siTIMPl_p84; siTIMPl_p86; siTIMPl_p87; siTIMPl_p88; siTIMPl_p90; siTIMPl_p92; siTIMPl_p93; siTIMPl_p94; siTIMPl_p95; siTIMPl_p97; siTIMPl_pl00; siTIMPl_pl01; siTIMPl_pl02; siTIMPl_pl03; siTIMPl_pl04; siTIMPl_pl05; siTIMPl_pl06;

siTIMPl_pl09; siTIMPl_pl 10; siTIMPl_pl 11; siTIMPl_pl 12; siTIMPl_pl l3 and siTIMPl_pl 14, shown in Table A7, infra.

[0050] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMPl_pl (SEQ ID NOS:845 and 926); siTIMPl_p4 (SEQ ID NOS:847 and 928; siTIMPl_p5 (SEQ ID NOS:848 and 929); siTIMPl_p7 (SEQ ID NOS:849 and 930); siTIMPl_p8 (SEQ ID NOS:850 and 931); siTIMPl_p9 (SEQ ID NOS:850 and 931); siTIMPl_pl0 (SEQ ID NOS:852 and 933); siTIMPl_pl l (SEQ ID NOS:853 and 934); siTIMPl_pl2 (SEQ ID NOS:854 and 935); siTIMPl_pl3 (SEQ ID NOS:855 and 936); siTIMPl_pl5 (SEQ ID NOS:856 and 937); siTIMPl_pl8 (SEQ ID NOS:857 and 938); siTIMPl_p22 (SEQ ID NOS:858 and 939); siTIMPl_p26 (SEQ ID NOS:860 and 941); siTIMPl_p36 (SEQ ID NOS:866 and 947); siTIMPl_p37 (SEQ ID NOS:867 and 948); siTIMPl_p39 (SEQ ID NOS:868 and 949); siTIMPl_p40 (SEQ ID NOS:869 and 950); siTIMPl_p41 (SEQ ID NOS:870 and 951); siTIMPl_p44 (SEQ ID NOS:871 and 952); siTIMPl_p47 (SEQ ID NOS:873 and 954); siTIMPl_p48 (SEQ ID NOS:874 and 955); siTIMPl_p50 (SEQ ID NOS:875 and 956); siTIMPl_p51 (SEQ ID NOS:876 and 957); siTIMPl_p52 (SEQ ID NOS:877 and 958); siTIMPl_p55 (SEQ ID NOS:880 and 961); siTIMPl_p56 (SEQ ID NOS:881 and 962); siTIMPl_p58 (SEQ ID NOS:883 and 964); siTIMPl_p61 (SEQ ID NOS:885 and 966); siTIMPl_p64 (SEQ ID NOS:888 and 969); siTIMPl_p66 (SEQ ID NOS:890 and 971); siTIMPl_p68 (SEQ ID NOS:892 and 973); siTIMPl_p70 (SEQ ID NOS:894 and 975); siTIMPl_p75 (SEQ ID NOS:897 and 978); siTIMPl_p83 (SEQ ID NOS:902 and 983); siTIMPl_p86 (SEQ ID NOS:904 and 985); siTIMPl_p88 (SEQ ID NOS:906 and 987); siTIMPl_p92 (SEQ ID NOS:908 and 989); siTIMPl_p93 (SEQ ID NOS:909 and 990); siTIMPl_p95 (SEQ ID NOS:911 and 992); siTIMPl_p97 (SEQ ID NOS:912 and 993); siTIMPl_pl02 (SEQ ID NOS:915 and 996); siTIMPl_pl04 (SEQ ID NOS:917 and 998); siTIMPl_pl05 (SEQ ID NOS:918 and 999); siTIMPl_pl06 (SEQ ID NOS:919 and 1000); siTIMPl_pl l0 (SEQ ID NOS:921 and 1002) and siTIMPl_pl 12 (SEQ ID NOS:923 and 1004), shown in Table A8, infra.

[0051] In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl (SEQ ID NOS:845 and 926). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p4 (SEQ ID NOS:847 and 928. In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p5 (SEQ ID NOS:848 and 929). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p7 (SEQ ID NOS:849 and 930). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p8 (SEQ ID NOS:850 and 931). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p9 (SEQ ID NOS:850 and 931). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_plO (SEQ ID NOS:852 and 933). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl 1 (SEQ ID NOS:853 and 934). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl2 (SEQ ID NOS:854 and 935). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl3 (SEQ ID NOS:855 and 936). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl5 (SEQ ID NOS:856 and 937). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl8 (SEQ ID NOS:857 and 938). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p22 (SEQ ID NOS:858 and 939). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p26 (SEQ ID NOS:860 and 941). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p36 (SEQ ID NOS:866 and 947). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p37 (SEQ ID NOS:867 and 948). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p39 (SEQ ID NOS:868 and 949). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p40 (SEQ ID NOS:869 and 950). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p41 (SEQ ID NOS:870 and 951). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p44 (SEQ ID NOS:871 and 952). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p47 (SEQ ID NOS:873 and 954). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p48 (SEQ ID NOS:874 and 955). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p50 (SEQ ID NOS:875 and 956). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p51 (SEQ ID NOS:876 and 957). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p52 (SEQ ID NOS:877 and 958). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p55 (SEQ ID NOS:880 and 961). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p56 (SEQ ID NOS:881 and 962). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p58 (SEQ ID NOS:883 and 964). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p61 (SEQ ID NOS:885 and 966). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p64 (SEQ ID NOS:888 and 969). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p66 (SEQ ID NOS:890 and 971). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p68 (SEQ ID NOS:892 and 973). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p70 (SEQ ID NOS:894 and 975). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p75 (SEQ ID NOS:897 and 978). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p83 (SEQ ID NOS:902 and 983). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p86 (SEQ ID NOS:904 and 985). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p88 (SEQ ID NOS:906 and 987). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p92 (SEQ ID NOS:908 and 989). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p93 (SEQ ID NOS:909 and 990). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p95 (SEQ ID NOS:911 and 992). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_p97 (SEQ ID NOS:912 and 993). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl02 (SEQ ID NOS:915 and 996). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl04 (SEQ ID NOS:917 and 998). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl05 (SEQ ID NOS:918 and 999). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl06 (SEQ ID NOS:919 and 1000). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl _pl 10 (SEQ ID NOS:921 and 1002). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMPl_pl 12 (SEQ ID NOS:923 and 1004).

[0052] In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl (SEQ ID NOS:845 and 926). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p4 (SEQ ID NOS:847 and 928. In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p5 (SEQ ID NOS:848 and 929). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p7 (SEQ ID NOS:849 and 930). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p9 (SEQ ID NOS:850 and 931). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl0 (SEQ ID NOS:852 and 933). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pll (SEQ ID NOS:853 and 934). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl2 (SEQ ID NOS:854 and 935). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl3 (SEQ ID NOS:855 and 936). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl5 (SEQ ID NOS:856 and 937). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_pl8 (SEQ ID NOS:857 and 938). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p44 (SEQ ID NOS:871 and 952). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p48 (SEQ ID NOS:874 and 955). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p51 (SEQ ID NOS:876 and 957). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMPl_p52 (SEQ ID NOS:877 and 958).

[0053] In some embodiments (N)x has complementarity to a consecutive sequence in SEQ ID NO:2 (human TIMP2 mRNA). In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables B5, B6, B7, and B8. In some embodiments x=y=18 and Nl-(N)x includes an antisense oligonucleotide present in any one of Tables B3 or B4. In some embodiments x=y=19 or x=y=20. In certain preferred embodiments x =y=18.

[0054] In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table B5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B6. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table B6. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B7, and preferably from Table B8.

[0055] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_pl; siTIMP2_p2; siTIMP2_p3; siTIMP2_p5; siTIMP2_p6; siTIMP2_p7; siTIMP2_p8; siTIMP2_p9; siTIMP2_plO; siTIMP2_pl l; siTIMP2_pl2; siTIMP2_pl3; siTIMP2_pl4; siTIMP2_pl5; siTIMP2_pl9; siTIMP2_p21; siTIMP2_p22; siTIMP2_p23; siTIMP2_p26; siTIMP2_p28; siTIMP2_p31; siTIMP2_p32; siTIMP2_p34; siTIMP2_p36; siTIMP2_p42; siTIMP2_p43; siTIMP2_p45; siTIMP2_p47; siTIMP2_p48; siTIMP2_p49; siTIMP2_p50; siTIMP2_p52; siTIMP2_p53; siTIMP2_p54; siTIMP2_p56; siTIMP2_p57; siTIMP2_p58; siTIMP2_p59; siTIMP2_p60; siTIMP2_p63; siTIMP2_p66; siTIMP2_p70; siTIMP2_p72; siTIMP2_p73; siTIMP2_p74; siTIMP2_p77; siTIMP2_p80 and siTIMP2_p81, shown in Table B7, infra.

[0056] In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p6 (SEQ ID NOS:4771 and 4819); siTIMP2_p9 (SEQ ID NOS:4774 and 4822); siTIMP2_pl5 (SEQ ID NOS:4780 and 4828); siTIMP2_pl9 (SEQ ID NOS:4781 and 4829); siTIMP2_p21 (SEQ ID NOS:4782 and 4830); siTIMP2_p22 (SEQ ID NOS:4783 and 4831); siTIMP2_p23 (SEQ ID NOS:4784 and 4832); siTIMP2_p28 (SEQ ID NOS:4786 and 4834); siTIMP2_p31 (SEQ ID NOS:4787 and 4835); siTIMP2_p36 (SEQ ID NOS:4790 and 4838); siTIMP2_p42 (SEQ ID NOS:4791 and 4839); siTIMP2_p47 (SEQ ID NOS:4794 and 4842); siTIMP2_p50 (SEQ ID NOS:4797 and 4845); siTIMP2_p56 (SEQ ID NOS:4801 and 4849); siTIMP2_p57 (SEQ ID NOS:4802 and 4850); siTIMP2_p58 (SEQ ID NOS:4803 and 4851); siTIMP2_p60 (SEQ ID NOS:4805 and 4853); siTIMP2_p63 (SEQ ID NOS:4806 and 4854); siTIMP2_p70 (SEQ ID NOS:4808 and 4856); siTIMP2_p73 (SEQ ID NOS:4810 and 4858); siTIMP2_p74 (SEQ ID NOS:4811 and 4859); and siTIMP2_p81 (SEQ ID NOS:4814 and 4862), shown in Table B8, infra.

[0057] In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p6 (SEQ ID NOS:4771 and 4819). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p9 (SEQ ID NOS:4774 and 4822). In some

embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_pl5 (SEQ ID NOS:4780 and 4828). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_pl9 (SEQ ID NOS:4781 and 4829). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p21 (SEQ ID NOS:4782 and 4830). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p22 (SEQ ID NOS:4783 and 4831). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p23 (SEQ ID NOS:4784 and 4832). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p28 (SEQ ID NOS:4786 and 4834). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p31 (SEQ ID NOS:4787 and 4835). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p36 (SEQ ID NOS:4790 and 4838). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p42 (SEQ ID NOS:4791 and 4839). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p47 (SEQ ID NOS:4794 and 4842). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p50 (SEQ ID NOS:4797 and 4845). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p56 (SEQ ID NOS:4801 and 4849). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p57 (SEQ ID NOS:4802 and 4850). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p58 (SEQ ID NOS:4803 and 4851). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p60 (SEQ ID NOS:4805 and 4853). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p63 (SEQ ID NOS:4806 and 4854); siTIMP2_p70 (SEQ ID NOS:4808 and 4856). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p73 (SEQ ID NOS:4810 and 4858). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p74 (SEQ ID NOS:4811 and 4859). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p81 (SEQ ID NOS:4814 and 4862).

[0058] In some embodiments Nl and N2 form a Watson-Crick base pair. In other embodiments Nl and N2 form a non- Watson-Crick base pair. In some embodiments Nl is a modified riboadenosine or a modified ribouridine.

[0059] In certain embodiments Nl is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine. In other embodiments Nl is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine.

[0060] In certain embodiments Nl is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine and N2 is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine. In certain embodiments Nl is selected from the group consisting of riboadenosine and modified riboadenosine and N2 is selected from the group consisting of ribouridine and modified ribouridine.

[0061] In certain embodiments N2 is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine and Nl is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine. In certain embodiments Nl is selected from the group consisting of ribouridine and modified ribouridine and N2 is selected from the group consisting of riboadenine and modified riboadenine. In certain embodiments Nl is ribouridine and N2 is riboadenine.

[0062] In some embodiments of Structure (A2), Nl includes 2'OMe sugar-modified ribouracil or 2'OMe sugar-modified riboadenosine. In certain embodiments of structure (A), N2 includes a 2'OMe sugar modified ribonucleotide or deoxyribonucleotide.

[0063] In some embodiments Z and Z' are absent. In other embodiments one of Z or Z' is present.

[0064] In some embodiments each of N and N' is an unmodified nucleotide. In some embodiments at least one of N or N' includes a chemically modified nucleotide or an unconventional moiety. In some embodiments the unconventional moiety is selected from a mirror nucleotide, an abasic ribose moiety and an abasic deoxyribose moiety. In some embodiments the unconventional moiety is a mirror nucleotide, preferably an L-DNA moiety. In some embodiments at least one of N or N' includes a 2'OMe sugar-modified ribonucleotide.

[0065] In some embodiments the sequence of (N')y is fully complementary to the sequence of (N)x. In other embodiments the sequence of (N')y is substantially complementary to the sequence of (N)x.

[0066] In some embodiments (N)x includes an antisense sequence that is fully

complementary to about 17 to about 39 consecutive nucleotides in a target mRNA. In other embodiments (N)x includes an antisense that is substantially complementary to about 17 to about 39 consecutive nucleotides in a target mRNA. In some embodiments (N)x includes an antisense that is substantially complementary to about 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, to about 39 consecutive nucleotides in a target mRNA. In other embodiments (N)x includes an antisense that is substantially

complementary to about 17 to about 23, 18 to about 23, 18 to about 21, or 18 to about 19 consecutive nucleotides in a target mRNA.

[0067] In some embodiments of Structure Al and Structure A2 the compound is blunt ended, for example wherein both Z and Z' are absent. In an alternative embodiment, at least one of Z or Z' is present. Z and Z' independently include one or more covalently linked modified and or unmodified nucleotides, including deoxyribonucleotides and ribonucleotides, or an unconventional moiety for example inverted abasic deoxyribose moiety or abasic ribose moiety; a non-nucleotide C3, C4 or C5 moiety, an amino-6 moiety, a mirror nucleotide and the like. In some embodiments each of Z and Z' independently includes a C3 moiety or an amino-C6 moiety. In some embodiments Z' is absent and Z is present and includes a non-nucleotide C3 moiety. In some embodiments Z is absent and Z' is present and includes a non-nucleotide C3 moiety.

[0068] In some preferred embodiments of Structures Al and Structure A2 an asymmetrical siNA compound molecule has a 3' terminal non-nucleotide overhang (for example C3-C3 3 '-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In some preferred embodiments z' is present and the dsNA molecule has a 5 ' terminal non-nucleotide overhang (for example an abasic moiety) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule.

[0069] In some embodiments of Structure Al and Structure A2 each N consists of an unmodified ribonucleotide. In some embodiments of Structure Al and Structure A2 each N' consists of an unmodified nucleotide. In preferred embodiments, at least one of N and N' is a modified ribonucleotide or an unconventional moiety.

[0070] In other embodiments the compound of Structure Al or Structure A2 includes at least one ribonucleotide modified in the sugar residue. In some embodiments the compound includes a modification at the 2' position of the sugar residue. In some embodiments the modification in the 2' position includes the presence of an amino, a fluoro, an alkoxy or an alkyl moiety. In certain embodiments the 2' modification includes an alkoxy moiety. In preferred embodiments the alkoxy moiety is a methoxy moiety (also known as 2'-0-methyl; 2'OMe; 2'-OCH3). In some embodiments the nucleic acid compound includes 2'OMe sugar modified alternating ribonucleotides in one or both of the antisense and the sense strands. In other embodiments the compound includes 2'OMe sugar modified ribonucleotides in the antisense strand, (N)x or Nl-(N)x, only. In certain embodiments the middle ribonucleotide of the antisense strand; e.g. ribonucleotide in position 10 in a 19-mer strand is unmodified. In various embodiments the nucleic acid compound includes at least 5 alternating 2'OMe sugar modified and unmodified ribonucleotides. [0071] In additional embodiments the compound of Structure Al or Structure A2 includes modified ribonucleotides in alternating positions wherein each ribonucleotide at the 5 ' and 3' termini of (N)x or Nl-(N)x are modified in their sugar residues, and each ribonucleotide at the 5' and 3' termini of (N')y or N2-(N)y are unmodified in their sugar residues.

[0072] In some embodiments, (N)x or Nl-(N)x includes 2'OMe modified ribonucleotides at positions 2, 4, 6, 8, 11, 13, 15, 17 and 19. In other embodiments (N)x (N)x or Nl-(N)x includes 2'OMe modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19. In some embodiments (N)x or Nl-(N)x includes 2'OMe modified pyrimidines. In some embodiments all the pyrimidine nucleotides in (N)x or Nl-(N)x are 2'OMe modified. In some embodiments (N')y or N2-(N')y includes 2'OMe modified pyrimidines.

[0073] In additional embodiments the compound of Structure Al or Structure A2 includes modified ribonucleotides in alternating positions wherein each ribonucleotide at the 5 ' and 3' termini of (N)x or Nl-(N)x are modified in their sugar residues, and each ribonucleotide at the 5' and 3' termini of (N')y or N2-(N)y are unmodified in their sugar residues.

[0074] In some embodiments of Structure Al and Structure A2, neither of the sense strand nor the antisense strand is phosphorylated at the 3' and 5' termini. In other embodiments one or both of the sense strand or the antisense strand are phosphorylated at the 3' termini.

[0075] In some embodiments of Structure Al and Structure A2 (N)y includes at least one unconventional moiety selected from a mirror nucleotide and a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate bond also known as 2 '-5' linked or 2'-5' linkage. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-R A) and an L-deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA.

[0076] In some embodiments of Structure Al (N')y includes at least one L-DNA moiety. In some embodiments x=y=19 and (N')y, consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3' penultimate position (position 18). In other embodiments x=y=19 and (N')y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3' penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2'-5' internucleotide phosphate linkage. According to various embodiments (N')y includes 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3' terminus linked by 2'-5' internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3' terminus of (N')y are joined by three 2 '-5' phosphodiester bonds, wherein one or more of the 2 '-5' nucleotides which form the 2 '-5' phosphodiester bonds further includes a 3'-0- methyl (3'OMe) sugar modification. Preferably the 3' terminal nucleotide of (N')y includes a 2'OMe sugar modification. In certain embodiments x=y=19 and (N')y includes two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 include a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide bond. In various embodiments the nucleotide forming the 2 '-5' internucleotide bond includes a 3' deoxyribose nucleotide or a 3' methoxy nucleotide. In some embodiments x=y=19 and (N')y includes nucleotides joined to the adjacent nucleotide by a 2'-5 ' internucleotide bond between positions 15-16, 16-17 and 17-18 or between positions 16-17, 17-18 and 18-19. In some embodiments x=y=19 and (N')y includes nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N')y are substituted with nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond.

[0077] In some embodiments of Structure A2, (N)y includes at least one L-DNA moiety. In some embodiments x=y=18 and (N')y consists of unmodified ribonucleotides at positions 1- 16 and 18 and one L-DNA at the 3' penultimate position (position 17). In other

embodiments x=y=18 and (N')y consists of unmodified ribonucleotides at position 1-15 and 18 and two consecutive L-DNA at the 3' penultimate position (positions 16 and 17). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate linkage. According to various embodiments (N')y includes 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3' terminus linked by 2'-5' internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3' terminus of (N')y are joined by three 2 '-5' phosphodiester bonds, wherein one or more of the 2 '-5' nucleotides which form the 2 '-5' phosphodiester bonds further includes a 3'-0- methyl (3'OMe) sugar modification. Preferably the 3' terminal nucleotide of (N')y includes a 2'OMe sugar modification. In certain embodiments x=y=18 and in (N')y two or more consecutive nucleotides at positions 14, 15, 16, 17, and 18 include a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide bond. In various embodiments the nucleotide forming the 2 '-5' internucleotide bond includes a 3' deoxyribose nucleotide or a 3' methoxy nucleotide. In some embodiments x=y=18 and (N')y includes nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond between positions 15-16, 16-17 and 17- 18 or between positions 16-17 and 17-18. In some embodiments x=y=18 and (N')y includes nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond between positions 14-15, 15-16, 16-17, and 17-18 or between positions 15-16, 16-17, and 17-18 or between positions 16-17 and 17-18 or between positions 17-18 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N')y are substituted with nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond.

[0078] In some embodiments, x=y=19 and (N')y comprises five consecutive nucleotides at the 3' terminus joined by four 2 '-5' linkages, specifically the linkages between the nucleotides position 15-16, 16-17, 17-18 and 18-19.

[0079] In some embodiments the internucleotide linkages include phosphodiester bonds. In some embodiments x=y=19 and (N')y comprises five consecutive nucleotides at the 3' terminus joined by four 2'-5' linkages and optionally further includes Z' and z'

independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

[0080] In some embodiments x=y=19 and (N')y comprises an L-DNA position 18; and (N')y optionally further includes Z' and z' independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono (dihydro gen phosphate)] cap.

[0081] In some embodiments (N')y comprises a 3' terminal phosphate. In some

embodiments (N')y comprises a 3' terminal hydroxyl.

[0082] In some embodiments x=y=19 and (N)x includes 2'OMe sugar modified

ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or at positions 2, 4, 6, 8, 11, 13, 15, 17, 19 . In some embodiments x=y=19 and (N)x includes 2'OMe sugar modified pyrimidines. In some embodiments all pyrimidines in (N)x include the 2'OMe sugar modification. [0083] In some embodiments x=y=18 and N2 is a riboadenine moiety.

[0084] In some embodiments in x=y=18, and N2-(N')y comprises five consecutive nucleotides at the 3 ' terminus joined by four 2 '-5 ' linkages, specifically the linkages between the nucleotides position 15-16, 16-17, 17-18 and 18-19. In some embodiments the linkages include phosphodiester bonds.

[0085] In some embodiments x=y=18 and N2-(N')y comprises five consecutive nucleotides at the 3' terminus joined by four 2'-5' linkages and optionally further includes Z' and z' independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

[0086] In some embodiments x=y=18 and N2-(N')y comprises an L-DNA position 18; and (N')y optionally further includes Z' and z' independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono (dihydro gen phosphate)] cap.

[0087] In some embodiments N2-(N')y comprises a 3' terminal phosphate. In some embodiments N2-(N')y comprises a 3' terminal hydroxyl.

[0088] In some embodiments x=y=18 and Nl-(N)x includes 2'OMe sugar modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or at positions 2, 4, 6, 8, 11, 13, 15, 17, 19 .

[0089] In some embodiments x=y=18 and Nl-(N)x includes 2'OMe sugar modified pyrimidines. In some embodiments all pyrimidines in (N)x include the 2'OMe sugar modification. In some embodiments Nl-(N)x further comprises an L-DNA at position 6 or 7 (5'>3'). In other embodiments Nl-(N)x further comprises a ribonucleotide which generates a 2'5' internucleotide linkage in between the ribonucleotides at positions 5-6 or 6-7 (5 '>3')

[0090] In additional embodiments Nl-(N)x further includes Z wherein Z comprises a non- nucleotide overhang. In some embodiments the non-nucleotide overhang is C3 -C3 [1,3- propanediol mono(dihydrogen phosphate)]2.

[0091] In some embodiments the double stranded molecules disclosed herein, in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8, include one or more of the following modifications: a) N in at least one of positions 5, 6, 7, 8, or 9 from the 5' terminus of the antisense strand is selected from a DNA, TNA, a 2'5' nucleotide or a mirror nucleotide; b) N' in at least one of positions 9 or 10 from the 5' terminus of the sense strand is selected from a TNA, 2 '5' nucleotide and a pseudoUridine; c) N' in 4, 5, or 6 consecutive positions at the 3' terminus positions of (N')y comprises a 2'5 ' nucleotide; d) one or more pyrimidine ribonucleotides are 2' modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

[0092] In some embodiments the double stranded molecules in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8 include a combination of the following modifications a) the antisense strand includes a DNA, TNA, a 2 '5' nucleotide or a mirror nucleotide in at least one of positions 5, 6, 7, 8, or 9 from the 5' terminus; b) the sense strand includes at least one of a TNA, a 2'5' nucleotide and a pseudoUridine in positions 9 or 10 from the 5' terminus; and c) one or more pyrimidine ribonucleotides are 2' modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

[0093] In some embodiments the double stranded molecules in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8 include a combination of the following modifications a) the antisense strand includes a DNA, 2'5' nucleotide or a mirror nucleotide in at least one of positions 5, 6, 7, 8, or 9 from the 5' terminus; b) the sense strand includes 4, 5, or 6 consecutive 2'5' nucleotides at the 3' penultimate or 3' terminal positions; and c) one or more pyrimidine ribonucleotides are 2' modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

[0094] In some embodiments of Structure Al and/or Structure A2 (N)y includes at least one unconventional moiety selected from a mirror nucleotide, a 2'5' nucleotide and a TNA. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-R A) and an L- deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA. In certain embodiments the sense strand comprises an unconventional moiety in position 9 or 10 (from the 5 ' terminus). In preferred embodiments the sense strand includes an unconventional moiety in position 9 (from the 5' terminus). In some embodiments the sense strand is 19 nucleotides in length and comprises 4, 5, or 6 consecutive unconventional moieties in positions 15, (from the 5' terminus). In some embodiments the sense strand includes 4 consecutive 2'5' ribonucleotides in positions 15, 16, 17, and 18. In some embodiments the sense strand includes 5 consecutive 2'5' ribonucleotides in positions 15, 16, 17, 18 and 19. In various embodiments the sense strand further comprises Z'. In some embodiments Z' includes a C30H moiety or a C3Pi moiety.

[0095] In some embodiments of Structure Al and/or Structure A2 (N)y comprises at least one unconventional moiety selected from a mirror nucleotide and a nucleotide joined to an adjacent nucleotide by a 2'-5' internucleotide phosphate bond. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-RNA) and an L-deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA.

[0096] In some embodiments of Structure Al (N')y comprises at least one L-DNA moiety. In some embodiments x=y=19 and (N')y consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3' penultimate position (position 18). In other embodiments x=y=19 and (N')y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3' penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate linkage. According to various embodiments (N')y comprises 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3' terminus linked by 2'- 5' internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3' terminus of (N')y are joined by three 2'-5' phosphodiester bonds. In one embodiment, five consecutive nucleotides at the 3' terminus of (N')y are joined by four 2'-5' phosphodiester bonds. In some embopdiments, wherein one or more of the 2'-5' nucleotides form a 2'-5' phosphodiester bonds the nucleotide further comprises a 3'-0-methyl (3'OMe) sugar modification. In some embodiments the 3' terminal nucleotide of (N')y comprises a 3'OMe sugar modification. In certain embodiments x=y=19 and (N')y comprises two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 comprise a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide bond. In various embodiments the nucleotide forming the 2 '-5' internucleotide bond comprises a 3' deoxyribose nucleotide or a 3' methoxy nucleotide. In some embodiments x=y=19 and (N')y comprises nucleotides joined to the adjacent nucleotide by a 2'-5 ' internucleotide bond between positions 15-16, 16-17 and 17-18 or between positions 16-17, 17-18 and 18-19. In some embodiments x=y=19 and (N')y comprises nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N')y are substituted with nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond.

[0097] In some embodiments of Structure A2 (N)y comprises at least one L-DNA moiety. In some embodiments x=y=18 and N2-(N')y, consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3' penultimate position (position 18). In other embodiments x=y=18 and N2-(N')y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3' penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate linkage. According to various embodiments N2-(N')y comprises 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3' terminus linked by 2 '-5' internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3' terminus of N2- (N')y are joined by three 2 '-5 ' phosphodiester bonds, wherein one or more of the 2'-5' nucleotides which form the 2'-5 ' phosphodiester bonds further comprises a 3 '- O-methyl (3'OMe) sugar modification. In some embodiments the 3' terminal nucleotide of N2-(N')y comprises a 2'OMe sugar modification. In certain embodiments x=y=18 and N2- (N')y comprises two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 comprise a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide bond. In various embodiments the nucleotide forming the 2 '-5' internucleotide bond comprises a 3' deoxyribose nucleotide or a 3' methoxy nucleotide. In some embodiments x=y=18 and N2- (N')y comprises nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N')y comprise nucleotides joined to the adjacent nucleotide by a 2'-5' internucleotide bond.

[0098] In further embodiments of Structures Al and A2 (N')y comprises 1-8 modified ribonucleotides wherein the modified ribonucleotide is a deoxyribose (DNA) nucleotide. In certain embodiments (N')y comprises 1, 2, 3, 4, 5, 6, 7, or up to 8 DNA moieties. In further embodiments of Structures Al and A2 (N')y includes 1-8 modified ribonucleotides wherein the modified ribonucleotide is a DNA nucleotide. In certain embodiments (N')y includes 1, 2, 3, 4, 5, 6, 7, or up to 8 DNA moieties.

[0099] In some embodiments either Z or Z' is present and independently includes two non- nucleotide moieties.

[00100] In additional embodiments Z and Z' are present and each independently includes two non-nucleotide moieties.

[00101] In some embodiments each of Z and Z' includes an abasic moiety, for example a deoxyriboabasic moiety (referred to herein as "dAb") or riboabasic moiety (referred to herein as "rAb"). In some embodiments each of Z and/or Z' includes two covalently linked abasic moieties and is for example dAb-dAb or rAb-rAb or dAb-rAb or rAb-dAb, wherein each moiety is covalently attached to an adjacent moiety, preferably via a phospho-based bond. In some embodiments the phospho-based bond includes a phosphorothioate, a phosphonoacetate or a phosphodiester bond. In preferred embodiments the phospho-based bond includes a phosphodiester bond.

[00102] In some embodiments each of Z and/or Z' independently includes an alkyl moiety, optionally propane [(CH2)3] moiety (C3) or a derivative thereof including propanol (C3- OH) and phospho derivative of propanediol ("C3-3'Pi"). In some embodiments each of Z and/or Z' includes two alkyl moieties and in some examples is C3-C3-OH. The 3' terminus of the antisense strand and/or the 3' terminus of the sense strand is covalently attached to a C3 moiety via a phospho-based bond and the C3 moiety is covalently conjugated a C3-OH moiety via a phospho-based bond. In some embodiments the phospho-based bonds include a phosphorothioate, a phosphonoacetate or a phosphodiester bond. In preferred embodiments the phospho-based bond includes a phosphodiester bond.

[00103] In one specific embodiment of Structure Al or Structure A2, Z includes C3-C3-OH (a propyl moiety covalently linked to a propanol moiety via a phosphodiester bond). In some embodiments Z includes a propanol moiety covalently attached to the 3 ' terminus of the antisense strand via a phosphodiester bond. In some embodiments the C3-C3-OH overhang is covalently attached to the 3' terminus of (N)x or (N')y via covalent linkage, for example a phosphodiester linkage. In some embodiments the linkage between a first C3 and a second C3 is a phosphodiester linkage.

[00104] In various embodiments the alkyl moiety is a C3 alkyl ("C3") to C6 alkyl ("C6") (e.g. C3, C4, C5 or C6) moiety including a terminal hydroxyl, a terminal amino, terminal phosphate group.

[00105] In some embodiments the alkyl moiety is a C3 alkyl moiety. In some embodiments the C3 alkyl moiety includes propanol, propylphosphate, propylphosphorothioate or a combination thereof.

[00106] The C3 alkyl moiety may be covalently linked to the 3' terminus of (N')y and or the 3 ' terminus of (N)x via a phosphodiester bond. In some embodiments the alkyl moiety includes propanol, propyl phosphate (trimethyl phosphate) or propyl phosphorothioate (trimethyl phosphorothioate).

[00107] In some embodiments each of Z and Z' is independently selected from propanol, propyl phosphate (trimethyl phosphate), propyl phosphorothioate (trimethyl

phosphorothioate), combinations thereof or multiples thereof.

[00108] In some embodiments each of Z and Z' is independently selected from propyl phosphate (trimethyl phosphate), propyl phosphorothioate (trimethyl phosphorothioate), propyl phospho-propanol; propyl phospho-propyl phosphorothioate; propylphospho-propyl phosphate; (propyl phosphate)3, (propyl phosphate)2 -propanol, (propyl phosphate)2- propyl phosphorothioate. Any propane or propanol conjugated moiety can be included in Z or Z'. [00109] In additional embodiments each of Z and/or Z' includes a combination of an abasic moiety and an unmodified deoxyribonucleotide or ribonucleotide or a combination of a hydrocarbon moiety and an unmodified deoxyribonucleotide or ribonucleotide or a combination of an abasic moiety (deoxyribo or ribo) and a hydrocarbon moiety. In such embodiments, each of Z and/or Z' includes C3-rAb or C3-dAb wherein each moiety is covalently bond to the adjacent moiety via a phospho-based bond, preferably a

phosphodiester, phosphorothioate or phosphonoacetate bond.

[00110] In certain embodiments nucleic acid molecules as disclosed herein include a sense oligonucleotide sequence selected from any one of Tables A1-B8.

[00111] In some embodiments, provided is a tandem structure and a triple armed structure, also known as R Astar. Such structures are disclosed in PCT patent publication WO 2007/091269. A tandem oligonucleotide comprises at least two siR A compounds.

[00112] A triple-stranded oligonucleotide may be an oligoribonucleotide having the general structure:

5' oligol (sense) LINKER A Oligo2 (sense) 3'

3' oligol (antisense) LINKER B Oligo3 (sense) 5'

3' oligo3 (antisense) LINKER C oligo2 (antisense) 5'

or

5' oligol (sense) LINKER A Oligo2 (antisense) 3'

3' oligol (antisense) LINKER B Oligo3 (sense) 5'

3' oligo3 (antisense) LINKER C oligo2 (sense) 5'

or

5' oligol (sense) LINKER A oligo3 (antisense) 3'

3' oligol (antisense) LINKER B oligo2 (sense) 5'

5' oligo3 (sense) LINKER C oligo2 (antisense) 3'

[00113] wherein one or more of linker A, linker B or linker C is present; any combination of two or more oligonucleotides and one or more of linkers A-C is possible, so long as the polarity of the strands and the general structure of the molecule remains. Further, if two or more of linkers A-C are present, they may be identical or different. [00114] In some embodiments a "gapped" RNAstar compound is preferred wherein the compound consists of four ribonucleotide strands forming three siRNA duplexes having the general structure as follows:

strand 1

strand 2

wherein each of oligo A, oligo B, oligo C, oligo D, oligo E and oligo F represents at least 19 consecutive ribonucleotides, wherein from 19 to 40 of such consecutive ribonucleotides, in each of oligo A, B, C, D, E and F comprise a strand of a siRNA duplex, wherein each ribonucleotide may be modified or unmodified; wherein strand 1 comprises oligo A which is either a sense portion or an antisense portion of a first siRNA duplex of the compound, strand 2 comprises oligo B which is complementary to at least 19 nucleotides in oligo A, and oligo A and oligo B together form a first siRNA duplex that targets a first target mRNA; wherein strand 1 further comprises oligo C which is either a sense portion or an antisense strand portion of a second siRNA duplex of the compound, strand 3 comprises oligo D which is complementary to at least 19 nucleotides in oligo C and oligo C and oligo D together form a second siRNA duplex that targets a second target mRNA; wherein strand 4 comprises oligo E which is either a sense portion or an antisense strand portion of a third siRNA duplex of the compound, strand 2 further comprises oligo F which is complementary to at least 19 nucleotides in oligo E and oligo E and oligo F together form a third siRNA duplex that targets a third target mRNA; and wherein linker A is a moiety that covalently links oligo A and oligo C; linker B is a moiety that covalently links oligo B and oligo F, and linker A and linker B can be the same or different.

[00115] In some embodiments the first, second and third siRNA duplex target the same gene, In other embodiments two of the first, second or third siRNA duplexes target the same mRNA and the third siRNA duplex targets a different mRNA. In some embodiments each of the first, second and third duplex targets a different mRNA.

[00116] In another aspect, provided are methods for reducing the expression of TIMP1 and TIMP2 in a cell by introducing into a cell a nucleic acid molecule as provided herein in an amount sufficient to reduce expression of TIMP1 and TIMP2. In one embodiment, the cell is hepatocellular stellate cell. In another embodiment, the cell is a stellate cell in renal or pulmonary tissue. In certain embodiments, the method is performed in vitro, in other embodiments, the method is performed in vivo.

[00117] In yet another aspect, provided are methods for treating an individual suffering from a disease associated with TIMP1 and /or TIMP2. The methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP1 or TIMP2. In certain embodiments the disease associated with TIMP1 or TIMP2 is a disease selected from the group consisting of liver fibrosis, cirrhosis, pulmonary fibrosis including lung fibrosis (including ILF), any condition causing kidney fibrosis (e.g., CKD including ESRD), peritoneal fibrosis, chronic hepatic damage, fibrillogenesis, fibrotic diseases in other organs, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma;

cardiofibrosis, fibrosis in the brain; failure of glaucoma filtering operation; and intestinal adhesions. The compounds are useful in treating organ specific indications including those shown in Table I below:

[00118] Table I

Malignancies Metastatic and invasive cancer by inhibiting function of activated tumor of various associated myofibroblasts

origin

[00119] In some embodiments the preferred indications include, Liver cirrhosis due to Hepatitis C post liver transplant; Liver cirrhosis due to Non- Alcoholic Steatohepatitis (NASH); Idiopathic Pulmonary Fibrosis (IPF); Radiation Pneumonitis leading to Pulmonary Fibrosis,; Diabetic Nephropathy; Peritoneal Sclerosis associated with continual ambulatory peritoneal dialysis (CAPD) and Ocular cicatricial pemphigoid.

[00120] Fibrotic Liver indications include Alcoholic Cirrhosis, Hepatitis B cirrhosis, Hepatitis C cirrhosis, Hepatitis C (Hep C) cirrhosis post orthotopic liver transplant (OLTX), NASH/NAFLD wherein NASH is an extreme form of nonalcoholic fatty liver disease (NAFLD), Primary biliary cirrhosis (PBC), Primary sclerosing cholangitis (PSC), Biliary atresia, alpha 1 antitrypsin deficiency (A IAD), Copper storage diseases (Wilson's disease), Fructosemia, Galactosemia, Glycogen storage diseases (especially types III, IV, VI, IX, and X), Iron-overload syndromes (hemochromatosis), Lipid abnormalities (e.g., Gaucher's disease). Peroxisomal disorders (eg, Zellweger syndrome), Tyrosinemia, Congenital hepatic fibrosis, Bacterial Infections (eg, brucellosis), Parasitic (eg, echinococcosis), Budd-Chiari syndrome (hepatic veno-occlusive disease).

[00121] Pulmonary Indications indications include Idiopathic Pulmonary Fibrosis, Silicosis, Pneumoconiosis, Bronchopulmonary Dysplasia in newborn following neonatal respiratory distress syndrome, Bleomycin/chemotherapeutic induced lung injury, Brochiolitis

Obliterans (BOS) post lung transplant, Chronic obstructive pulmonary disorder (COPD), Cystic Fibrosis, Asthma.

[00122] Cardiac indications include Cardiomyopathy, Atherosclerosis (Bergers disease, etc), Endomyocardial fibrosis, Atrial Fibrillation, Scarring post Myocardial Infarction (MI).

[00123] Other Thoracic indications include Radiation-induced capsule tissue reactions around textured breast implants and Oral submucosal fibrosis.

[00124] Renal indications include Autosomal Dominant Polycystic Kidney Disease

(ADPKD), Diabetic nephropathy (diabetic glomerulosclerosis), FSGS (collapsing vs. other histologic variants), IgA Nephropathy (Berger Disease), Lupus Nephritis, Wegner's, Scleroderma, Goodpasture Syndrome, tubulointerstitial fibrosis: drug induced (protective) pencillins, cephalosporins, analgesic nephropathy, Membranoproliferative

glomerulonephritis (MPGN), Henoch-Schonlein Purpura, Congenital nephropathies:

Medullary Cystic Disease, Nail-Patella Syndrome and Alport Syndrome.

[00125] Bone Marrow indications include lympangiolyomyositosis (LAM), Chronic graft vs. host disease, Polycythemia vera, Essential thrombocythemia, Myelofibrosis.

[00126] Ocular indications include Retinopathy of Prematurity (RoP), Ocular cicatricial pemphigoid, Lacrimal gland fibrosis, Retinal attachment surgery, Corneal opacity, Herpetic keratitis, Pterygia, Glaucoma, Age-related macular degeneration (AMD/ARMD), Retinal fibrosis associated Diabetes mellitus (DM) retinopathy.

[00127] Brain indications include fibrosis associated with brain infarction.

[00128] Gynecological indications include Endometriosis add on to hormonal therapy for prevention of scarring, post STD fibrosis/salphingitis.

[00129] Systemic indications include Dupuytren's disease, palmar fibromatosis, Peyronie's disease, Ledderhose disease, keloids, multifocal fibrosclerosis, nephrogenic systemic fibrosis, nephrogenic myelofibrosis (anemia).

[00130] Injury Associated Fibrotic Diseases include Burn (chemical included) induced skin & soft tissue scarring and contraction, Radiation induce skin & organ scarring post cancer therapeutic radiation treatment, Keloid (skin).

[00131] Surgical indications include peritoneal fibrosis post peritoneal dialysis catheter, corneal implant, cochlear implant, other implants , silicone implants in breasts, chronic sinusitis; adhesions, pseudointimal hyperplasia of dialysis grafts.

[00132] Other indications include Chronic Pancreatitis.

[00133] In some embodiments the methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP1. In some embodiments the methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP2. In some embodiments the methods include administering to the individual nucleic acid molecules such as provided herein in an amount sufficient to reduce expression of TIMP1. In some embodiments the methods include administering to the individual nucleic acid molecules such as provided herein in an amount sufficient to reduce expression of TIMP2. In some embodiments provided is a nucleic acid disclosed herein for the treatment of a fibrotic disease selected from a disease or disorder set forth in Table I. In another embodiment provided is a nucleic acid molecule for use in therapy. In some embodiments therapy comprises treatment of a fibrotic disease or disorder set forth in Table I. In some embodiments provided is use of a nucleic acid molecule disclosed herein for the preparation of a medicament useful in treating a fibrotic disease or disorder set forth in Table I. In some embodiments the nucleic acid molecule is set forth in Table C, e.g. TIMP1-A, TIMP1-B, TIMPl-C. In some embodiments the nucleic acid molecule is set forth in Table D, e.g. TIMP2-A, TIMP2-B, TIMP2-C, TIMP2-D, TIMP2-E. In some embodiments the sense and antisense sequences of the nucleic acid molecule are selected from the sequence pairs set forth in any one of Table A3, Table A4, Table A7 or Table A8. In some embodiments the sense and antisense sequences of the nucleic acid molecule are selected from the sequence pairs set forth in any one of Table B3, Table B4, Table B7 or Table B8.

[00134] In one aspect, provided are pharmaceutical compositions that include a nucleic acid molecule (e.g., an siNA molecule) as described herein in a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical formulation includes, or involves, a delivery system suitable for delivering nucleic acid molecules (e.g., siNA molecules) to an individual such as a patient; for example delivery systems described in more detail below.

[00135] In a related aspect, provided are compositions or kits that include a nucleic acid molecule (e.g., an siNA molecule) packaged for use by a patient. The package may be labeled or include a package label or insert that indicates the content of the package and provides certain information regarding how the nucleic acid molecule (e.g., an siNA molecule) should be or can be used by a patient, for example the label may include dosing information and/or indications for use. In certain embodiments the contents of the label will bear a notice in a form prescribed by a government agency, for example the United States Food and Drug Administration (FDA). In certain embodiments, the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating a patient suffering from a disease associated with TIMPl or TIMP2; for example, the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating fibroids; or for example the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating a disease selected from the group consisting of fibrosis, liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis.

[00136] As used herein, the term "tissue inhibitor of metalloproteinases 1" or "TIMPl" are used interchangeably and refer to any tissue inhibitor of metalloproteinases 1 peptide, or polypeptide having any TIMPl protein activity. Tissue inhibitor of metalloproteinases 1 is a natural inhibitor of matrix metalloproteinases. In certain preferred embodiments, "TIMPl" refers to human TIMPl . Tissue inhibitor of metalloproteinases 1 (or more particularly human TIMPl) may have an amino acid sequence that is the same, or substantially the same, as SEQ ID NO. 3 (Figure 1C).

[00137] As used herein, the term "tissue inhibitor of metalloproteinases 2" or "TIMP2" are used interchangeably and refer to any tissue inhibitor of metalloproteinases 2 peptide, or polypeptide having any TIMP2 protein activity. Tissue inhibitor of metalloproteinases 2 (or more particularly human TIMP2) may have an amino acid sequence that is the same, or substantially the same, as SEQ ID NO. 4 (Figure ID).

[00138] As used herein the term "nucleotide sequence encoding TIMPl and TIMP2" means a nucleotide sequence that codes for a TIMPl and TIMP2 protein or portion thereof. The term "nucleotide sequence encoding TIMPl and TIMP2" is also meant to include TIMPl and TIMP2 coding sequences such as TIMPl and TIMP2 iso forms, mutant TIMPl and TIMP2 genes, splice variants of TIMPl and TIMP2 genes, and TIMPl and TIMP2 gene polymorphisms. A nucleic acid sequence encoding TIMPl and TIMP2 includes mRNA sequences encoding TIMPl and TIMP2, which can also be referred to as "TIMPl and TIMP2 mRNA." Exemplary sequences of human TIMPl mRNA and TIMP2 mRNA are set forth as SEQ ID. NO. 1 and SEQ ID NO:2, respectively.

[00139] As used herein, the term "nucleic acid molecule" or "nucleic acid" are used interchangeably and refer to an oligonucleotide, nucleotide or polynucleotide. Variations of "nucleic acid molecule" are described in more detail herein. A nucleic acid molecule encompasses both modified nucleic acid molecules and unmodified nucleic acid molecules as described herein. A nucleic acid molecule may include deoxyribonucleotides, ribonucleotides, modified nucleotides or nucleotide analogs in any combination.

[00140] As used herein, the term "nucleotide" refers to a chemical moiety having a sugar (or an analog thereof, or a modified sugar), a nucleotide base (or an analog thereof, or a modified base), and a phosphate group (or analog thereof, or a modified phosphate group). A nucleotide encompasses both modified nucleotides or unmodified nucleotides as described herein. As used herein, nucleotides may include deoxyribonucleotides (e.g., unmodified deoxyribonucleotides), ribonucleotides (e.g., unmodified ribonucleotides), and modified nucleotide analogs including, inter alia, locked nucleic acids and unlocked nucleic acids, peptide nucleic acids, L-nucleotides (also referred to as mirror nucleotides), ethylene- bridged nucleic acid (ENA), arabinoside, PACE, nucleotides with a 6 carbon sugar, as well as nucleotide analogs (including abasic nucleotides) often considered to be non-nucleotides. In some embodiments, nucleotides may be modified in the sugar, nucleotide base and/or in the phosphate group with any modification known in the art, such as modifications described herein. A "polynucleotide" or "oligonucleotide" as used herein refer to a chain of linked nucleotides; polynucleotides and oligonucleotides may likewise have modifications in the nucleotide sugar, nucleotide bases and phosphate backbones as are well known in the art and/or are disclosed herein.

[00141] As used herein, the term "short interfering nucleic acid", "siNA", or "short interfering nucleic acid molecule" refers to any nucleic acid molecule capable of modulating gene expression or viral replication. Preferably siNA inhibits or down regulates gene expression or viral replication. siNA includes without limitation nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically-modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. As used herein, "short interfering nucleic acid", "siNA", or "short interfering nucleic acid molecule" has the meaning described in more detail elsewhere herein. [00142] As used herein, the term "complementary" means that a nucleic acid can form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules disclosed herein, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., R Ai activity. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al, 1987, CSH Symp. Quant. Biol. LII pp. 123-133; Frier et al, 1986, Proc. Nat. Acad. Sci. USA 83 :9373-9377; Turner et al, 1987, J. Am. Chem. Soc. 109:3783- 3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10 nucleotides in the first oligonucleotide being based paired to a second nucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%>, 80%>, 90%>, and 100% complementary respectively). "Fully complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. In one embodiment, a nucleic acid molecule disclosed herein includes about 15 to about 35 or more (e.g., about 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34 or 35 or more) nucleotides that are complementary to one or more target nucleic acid molecules or a portion thereof.

[00143] As used herein, the term "sense region" refers to a nucleotide sequence of a siNA molecule complementary (partially or fully) to an antisense region of the siNA molecule. The sense strand of a siNA molecule can include a nucleic acid sequence having homology with a target nucleic acid sequence. As used herein, "sense strand" refers to nucleic acid molecule that includes a sense region and may also include additional nucleotides.

[00144] As used herein, the term "antisense region" refers to a nucleotide sequence of a siNA molecule complementary (partially or fully) to a target nucleic acid sequence. The antisense strand of a siNA molecule can optionally include a nucleic acid sequence complementary to a sense region of the siNA molecule. As used herein, "antisense strand" refers to nucleic acid molecule that includes an antisense region and may also include additional nucleotides. [00145] As used herein, the term "R A" refers to a molecule that includes at least one ribonucleotide residue.

[00146] As used herein, the term "duplex region" refers to the region in two complementary or substantially complementary oligonucleotides that form base pairs with one another, either by Watson-Crick base pairing or any other manner that allows for a duplex between oligonucleotide strands that are complementary or substantially complementary. For example, an oligonucleotide strand having 21 nucleotide units can base pair with another oligonucleotide of 21 nucleotide units, yet only 19 bases on each strand are complementary or substantially complementary, such that the "duplex region" consists of 19 base pairs. The remaining base pairs may, for example, exist as 5' and 3' overhangs. Further, within the duplex region, 100% complementarity is not required; substantial complementarity is allowable within a duplex region. Substantial complementarity refers to complementarity between the strands such that they are capable of annealing under biological conditions. Techniques to empirically determine if two strands are capable of annealing under biological conditions are well know in the art. Alternatively, two strands can be synthesized and added together under biological conditions to determine if they anneal to one another.

[00147] As used herein, the terms "non-pairing nucleotide analog" means a nucleotide analog which includes a non-base pairing moiety including but not limited to: 6 des amino adenosine (Nebularine), 4-Me-indole, 3-nitropyrrole, 5-nitroindole, Ds, Pa, N3-Me ribo U, N3-Me riboT, N3-Me dC, N3-Me-dT, Nl-Me-dG, Nl-Me-dA, N3-ethyl-dC, N3-Me dC. In some embodiments the non-base pairing nucleotide analog is a ribonucleotide. In other embodiments it is a deoxyribonucleotide.

[00148] As used herein, the term, "terminal functional group" includes without limitation a halogen, alcohol, amine, carboxylic, ester, amide, aldehyde, ketone, ether groups.

[00149] An "abasic nucleotide" or "abasic nucleotide analog" is as used herein may also be often referred to herein and in the art as a pseudo-nucleotide or an unconventional moiety. While a nucleotide is a monomeric unit of nucleic acid, generally consisting of a ribose or deoxyribose sugar, a phosphate, and a base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA). an abasic or pseudo-nucleotide lacks a base, and thus is not strictly a nucleotide as the term is generally used in the art. Abasic deoxyribose moieties include for example, abasic deoxyribose-3 ' -phosphate; 1,2-dideoxy- D-ribofuranose-3 -phosphate; l,4-anhydro-2-deoxy-D-ribitol-3-phosphate. Inverted abasic deoxyribose moieties include inverted deoxyriboabasic; 3 ',5' inverted deoxyabasic 5'- phosphate.

[00150] The term "capping moiety" (z") as used herein includes a moiety which can be covalently linked to the 5' terminus of (N')y and includes abasic ribose moiety, abasic deoxyribose moiety, modifications abasic ribose and abasic deoxyribose moieties including 2' O alkyl modifications; inverted abasic ribose and abasic deoxyribose moieties and modifications thereof; C6-imino-Pi; a mirror nucleotide including L-DNA and L-RNA; 5'OMe nucleotide; and nucleotide analogs including 4',5 '-methylene nucleotide; 1-(β-ϋ- erythrofuranosyl)nucleotide; 4'-thio nucleotide, carbocyc lie nucleotide; 5'-amino-alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 12-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; alpha-nucleotide; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5 '-5 '-inverted abasic moiety; 1 ,4-butanediol phosphate; 5'-amino; and bridging or non bridging

methylphosphonate and 5'-mercapto moieties.

[00151] Certain capping moieties may be abasic ribose or abasic deoxyribose moieties; inverted abasic ribose or abasic deoxyribose moieties; C6-amino-Pi; a mirror nucleotide including L-DNA and L-RNA. The nucleic acid molecules as disclosed herein may be synthesized using one or more inverted nucleotides, for example inverted thymidine or inverted adenine (for example see Takei, et al., 2002. JBC 277(26):23800-06).

[00152] The term "unconventional moiety" as used herein refers to non-nucleotide moieties including an abasic moiety, an inverted abasic moiety, a hydrocarbon (alkyl) moiety and derivatives thereof, and further includes a deoxyribonucleotide, a modified

deoxyribonucleotide, a mirror nucleotide (L-DNA or L-RNA), a non-base pairing nucleotide analog and a nucleotide joined to an adjacent nucleotide by a 2'-5' internucleotide phosphate bond; bridged nucleic acids including LNA and ethylene bridged nucleic acids, linkage modified (e.g. PACE) and base modified nucleotides as well as additional moieties explicitly disclosed herein as unconventional moieties. [00153] As used herein, the term "inhibit", "down-regulate", or "reduce" with respect to gene expression means the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits (e.g., mRNA), or activity of one or more proteins or protein subunits, is reduced below that observed in the absence of an inhibitory factor (such as a nucleic acid molecule, e.g., an siNA, for example having structural features as described herein); for example the expression may be reduced to 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or less than that observed in the absence of an inhibitor.

BRIEF DESCRIPTION OF THE FIGURES

[00154] Figures 1A-1D show exemplary polynucleotide and polypeptide sequences. Fig. 1A shows mRNA sequence of human TIMPl (NM_003254.2 GL73858576; SEQ ID NO:l). Fig. IB shows mRNA sequence of TIMP2 (NM_003255.4 GL738585774; SEQ ID NO:2). Fig. 1C shows polypeptide sequence of human TIMPl (NP 003245.1 GL4507509; SEQ ID NO:3). Fig. ID shows polypeptide sequence of human TIMP2 (NP 003246.1 GL4507511; SEQ ID NO:4).

[00155] Figure 2 shows knock down efficacy as determined by qPCR of TIMPl -A, TIMPl - B or TIMPl -C siRNAs (Table C) for TIMPl. The siRNA compounds were capable of knocking down the target TIMPl gene.

[00156] Figure 3 shows knock down efficacy as determined by qPCR TIMP2-A, TIMP2-B, TIMP2-C, TIMP2-D and TIMP2-E siRNAs (Table D). The siRNA compounds were capable of knocking down the target TIMP2 gene.

[00157] Figure 4 shows the results of an in vivo assay testing the efficacy of siTIMPl and siTIMP2 in treating liver fibrosis. Analysis of the liver fibrosis area was performed using Sirius red staining. The fibrotic area was calculated as the mean of 4 liver sections. The bar graph summarizes the digital quantification of staining for each group. DETAILED DESCRIPTION OF THE INVENTION

RNA Interference and siNA Nucleic Acid Molecules

[00158] RNA interference refers to the process of sequence-specific post-transcriptional gene silencing in animals mediated by short interfering RNAs (siRNAs) (Zamore et al., 2000, Cell, 101, 25-33; Fire et al, 1998, Nature, 391, 806; Hamilton et al, 1999, Science, 286, 950-951; Lin et al, 1999, Nature, 402, 128-129; Sharp, 1999, Genes & Dev., 13: 139- 141; and Strauss, 1999, Science, 286, 886). The corresponding process in plants (Heifetz et al., International PCT Publication No. WO 99/61631) is often referred to as post- transcriptional gene silencing (PTGS) or RNA silencing. The process of post-transcriptional gene silencing is thought to be an evolutionarily-conserved cellular defense mechanism used to prevent the expression of foreign genes (Fire et al, 1999, Trends Genet., 15, 358). Such protection from foreign gene expression may have evolved in response to the production of double-stranded RNAs (dsRNAs) derived from viral infection or from the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single-stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response through a mechanism that has yet to be fully characterized. This mechanism appears to be different from other known mechanisms involving double stranded RNA-specific ribonucleases, such as the interferon response that results from dsRNA-mediated activation of protein kinase PKR and 2',5'-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L (see for example U.S. Pat. Nos. 6,107,094; 5,898,031; Clemens et al, 1997, J. Interferon & Cytokine Res., 17, 503-524; Adah et al, 2001, Curr. Med. Chem., 8, 1189).

[00159] The presence of long dsRNAs in cells stimulates the activity of a ribonuclease III enzyme referred to as dicer (Bass, 2000, Cell, 101, 235; Zamore et al, 2000, Cell, 101, 25- 33; Hammond et al, 2000, Nature, 404, 293). Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNAs) (Zamore et al, 2000, Cell, 101, 25-33; Bass, 2000, Cell, 101, 235; Berstein et al, 2001, Nature, 409, 363). Short interfering RNAs derived from dicer activity are typically about 21 to about 23 nucleotides in length and include about 19 base pair duplexes (Zamore et al., 2000, Cell, 101, 25-33; Elbashir et al, 2001, Genes Dev., 15, 188). Dicer has also been implicated in the excision of 21- and 22-nucleotide small temporal RNAs (stRNAs) from precursor RNA of conserved structure that are implicated in translational control (Hutvagner et al., 2001, Science, 293, 834). The RNAi response also features an endonuclease complex, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex (Elbashir et al, 2001, Genes Dev., 15, 188).

[00160] RNAi has been studied in a variety of systems. Fire et al, 1998, Nature, 391, 806, were the first to observe RNAi in C. elegans. Bahramian and Zarbl, 1999, Molecular and Cellular Biology, 19, 274-283 and Wianny and Goetz, 1999, Nature Cell Biol, 2, 70, describe RNAi mediated by dsRNA in mammalian systems. Hammond et al., 2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al, 2001, Nature, 411, 494 and Tuschl et al, International PCT Publication No. WO 01/75164, describe RNAi induced by introduction of duplexes of synthetic 21 -nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates (Elbashir et al., 2001, EMBO J., 20, 6877 and Tuschl et al., International PCT Publication No. WO 01/75164) has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity.

[00161] Nucleic acid molecules (for example having structural features as disclosed herein) may inhibit or down regulate gene expression or viral replication by mediating RNA interference "RNAi" or gene silencing in a sequence-specific manner; see e.g., Zamore et al, 2000, Cell, 101, 25-33; Bass, 2001, Nature, 41 1, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al, International PCT Publication No. WO 00/44895;

Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al, International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps- Depaillette, International PCT Publication No. WO 99/07409; and Li et al, International PCT Publication No. WO 00/44914; Allshire, 2002, Science, 297, 1818-1819; Volpe et al, 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al, 2002, Science, 297, 2232-2237; Hutvagner and Zamore, 2002, Science, 297, 2056-60; McManus et al, 2002, RNA, 8, 842-850; Reinhart et al, 2002, Gene & Dev., 16, 1616- 1626; and Reinhart & Barrel, 2002, Science, 297, 1831).

[00162] An siNA nucleic acid molecule can be assembled from two separate polynucleotide strands, where one strand is the sense strand and the other is the antisense strand in which the antisense and sense strands are self-complementary (i.e. each strand includes nucleotide sequence that is complementary to nucleotide sequence in the other strand); such as where the antisense strand and sense strand form a duplex or double stranded structure having any length and structure as described herein for nucleic acid molecules as provided, for example wherein the double stranded region (duplex region) is about 15 to about 49 (e.g., about 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 base pairs); the antisense strand includes nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule (i.e., TIMP1 and TIMP2 mRNA) or a portion thereof and the sense strand includes nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof (e.g., about 17 to about 49 or more nucleotides of the nucleic acid molecules herein are complementary to the target nucleic acid or a portion thereof).

[00163] In certain aspects and embodiments a nucleic acid molecule (e.g., a siNA molecule) provided herein may be a "RISC length" molecule or may be a Dicer substrate as described in more detail below.

[00164] An siNA nucleic acid molecule may include separate sense and antisense sequences or regions, where the sense and antisense regions are covalently linked by nucleotide or non- nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der Waals interactions, hydrophobic interactions, and/or stacking interactions. Nucleic acid molecules may include a nucleotide sequence that is complementary to nucleotide sequence of a target gene. Nucleic acid molecules may interact with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene.

[00165] Alternatively, an siNA nucleic acid molecule is assembled from a single polynucleotide, where the self-complementary sense and antisense regions of the nucleic acid molecules are linked by means of a nucleic acid based or non-nucleic acid-based linker(s), i.e., the antisense strand and the sense strand are part of one single polynucleotide that having an antisense region and sense region that fold to form a duplex region (for example to form a "hairpin" structure as is well known in the art). Such siNA nucleic acid molecules can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region includes nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence (e.g., a sequence of TIMP1 and TIMP2 mRNA). Such siNA nucleic acid molecules can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region includes nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active nucleic acid molecule capable of mediating RNAi.

[00166] The following nomenclature is often used in the art to describe lengths and overhangs of siNA molecules and may be used throughout the specification and Examples. Names given to duplexes indicate the length of the oligomers and the presence or absence of overhangs. For example, a "21+2" duplex contains two nucleic acid strands both of which are 21 nucleotides in length, also termed a 21-mer siRNA duplex or a 21-mer nucleic acid and having a 2 nucleotides 3 '-overhang. A "21-2" design refers to a 21-mer nucleic acid duplex with a 2 nucleotides 5 '-overhang. A 21-0 design is a 21-mer nucleic acid duplex with no overhangs (blunt). A "21+2UU" is a 21-mer duplex with 2- nucleotides 3'- overhang and the terminal 2 nucleotides at the 3 '-ends are both U residues (which may result in mismatch with target sequence). The aforementioned nomenclature can be applied to siNA molecules of various lengths of strands, duplexes and overhangs (such as 19-0, 21+2, 27+2, and the like). In an alternative but similar nomenclature, a "25/27" is an asymmetric duplex having a 25 base sense strand and a 27 base antisense strand with a 2- nucleotides 3 '-overhang. A "27/25" is an asymmetric duplex having a 27 base sense strand and a 25 base antisense strand. Chemical Modifications

[00167] In certain aspects and embodiments, nucleic acid molecules (e.g., siNA molecules) as provided herein include one or more modifications (or chemical modifications). In certain embodiments, such modifications include any changes to a nucleic acid molecule or polynucleotide that would make the molecule different than a standard ribonucleotide or R A molecule (i.e., that includes standard adenine, cytosine, uracil, or guanine moieties); which may be referred to as an "unmodified" ribonucleotide or unmodified ribonucleic acid. Traditional DNA bases and polynucleotides having a 2'-deoxy sugar represented by adenine, cytosine, thymine, or guanine moieties may be referred to as an "unmodified deoxyribonucleotide" or "unmodified deoxyribonucleic acid"; accordingly, the term

"unmodified nucleotide" or "unmodified nucleic acid" as used herein refers to an

"unmodified ribonucleotide" or "unmodified ribonucleic acid" unless there is a clear indication to the contrary. Such modifications can be in the nucleotide sugar, nucleotide base, nucleotide phosphate group and/or the phosphate backbone of a polynucleotide.

[00168] In certain embodiments modifications as disclosed herein may be used to increase R Ai activity of a molecule and/or to increase the in vivo stability of the molecules, particularly the stability in serum, and/or to increase bioavailability of the molecules. Non- limiting examples of modifications include without limitation internucleotide or

internucleoside linkages; deoxyribonucleotides or dideoxyribonucleotides at any position and strand of the nucleic acid molecule; nucleic acid (e.g., ribonucleic acid) with a modification at the 2'-position preferably selected from an amino, fluoro, methoxy, alkoxy and alkyl; 2 '-deoxyribonucleotides, 2'-0-methyl ribonucleotides, 2 '-deoxy-2' -fluoro ribonucleotides, "universal base" nucleotides, "acyclic" nucleotides, 5-C-methyl

nucleotides, biotin group, and terminal glyceryl and/or inverted deoxy abasic residue incorporation, sterically hindered molecules, such as fluorescent molecules and the like. Other nucleotides modifiers could include 3'-deoxyadenosine (cordycepin), 3'-azido-3'- deoxythymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxy-3'-thiacytidine (3TC), 2',3'-didehydro-2',3'-dideoxythymidi- ne (d4T) and the monophosphate nucleotides of 3'- azido-3'-deoxythymidine (AZT), 2',3'-dideoxy-3'-thiacytidine (3TC) and 2',3 '-didehydro- 2',3'-dide-oxythymidine (d4T). Further details on various modifications are described in more detail below. [00169] Modified nucleotides include those having a Northern conformation (e.g., Northern pseudorotation cycle, see for example Saenger, Principles of Nucleic Acid Structure, Springer- Verlag ed., 1984). Non-limiting examples of nucleotides having a northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2'-0, 4'-C-methylene- (D-ribofuranosyl) nucleotides); 2'-methoxyethoxy (MOE) nucleotides; 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoro nucleotides, 2'-deoxy-2'-chloro nucleotides, 2'-azido nucleotides, and 2'-0-methyl nucleotides. Locked nucleic acids, or LNA's are described, for example, in Elman et al., 2005; Kurreck et al., 2002; Crinelli et al., 2002; Braasch and Corey, 2001; Bondensgaard et al., 2000; Wahlestedt et al., 2000; and International Patent Publication Nos. WO 00/47599, WO 99/14226, and WO 98/39352 and WO 2004/083430. In one

embodiment, an LNA is incorporated at the 5' terminus of the sense strand.

[00170] Chemical modifications also include unlocked nucleic acids, or UNAs, which are non-nucleotide, acyclic analogues, in which the C2'-C3' bond is not present (although UNAs are not truly nucleotides, they are expressly included in the scope of "modified" nucleotides or modified nucleic acids as contemplated herein). In particular embodiments, nucleic acid molecules with an overhang may be modified to have UNAs at the overhang positions (i.e., 2 nucleotide overhand). In other embodiments, UNAs are included at the 3'- or 5'- ends. A UNA may be located anywhere along a nucleic acid strand, i.e. at position 7. Nucleic acid molecules may contain one or more than UNA. Exemplary UNAs are disclosed in Nucleic Acids Symposium Series No. 52 p. 133-134 (2008). In certain embodiments a nucleic acid molecule (e.g., a siNA molecule) as described herein include one or more UNAs; or one UNA. In some embodiments, a nucleic acid molecule (e.g., a siNA molecule) as described herein that has a 3 '-overhang include one or two UNAs in the 3' overhang. In some embodiments a nucleic acid molecule (e.g., a siNA molecule) as described herein includes a UNA (for example one UNA) in the antisense strand; for example in position 6 or position 7 of the antisense strand. Chemical modifications also include non-pairing nucleotide analogs, for example as disclosed herein. Chemical modifications further include unconventional moieties as disclosed herein.

[00171] Chemical modifications also include terminal modifications on the 5' and/or 3' part of the oligonucleotides and are also known as capping moieties. Such terminal modifications are selected from a nucleotide, a modified nucleotide, a lipid, a peptide, and a sugar. [00172] Chemical modifications also include six membered "six membered ring nucleotide analogs." Examples of six -membered ring nucleotide analogs are disclosed in Allart, et al (Nucleosides & Nucleotides, 1998, 17: 1523-1526,; and Perez-Perez, et al, 1996, Bioorg. and Medicinal Chem Letters 6: 1457-1460) Oligonucleotides including 6-membered ring nucleotide analogs including hexitol and altritol nucleotide monomers are disclosed in International patent application publication No. WO 2006/047842.

[00173] Chemical modifications also include "mirror" nucleotides which have a reversed chirality as compared to normal naturally occurring nucleotide; that is a mirror nucleotide may be an "L-nucleotide" analogue of naturally occurring D-nucleotide (see US Patent No. 6,602,858). Mirror nucleotides may further include at least one sugar or base modification and/or a backbone modification, for example, as described herein, such as a

phosphorothioate or phosphonate moiety. US Patent No. 6,602,858 discloses nucleic acid catalysts including at least one L-nucleotide substitution. Mirror nucleotides include for example L-DNA (L-deoxyriboadenosine-3 '-phosphate (mirror dA); L-deoxyribocytidine-3'- phosphate (mirror dC); L-deoxyriboguanosine-3 '-phosphate (mirror dG); L- deoxyribothymidine-3 '-phosphate (mirror image dT)) and L-RNA (L-riboadenosine-3'- phosphate (mirror rA); L-ribocytidine-3 ' -phosphate (mirror rC); L-riboguanosine-3'- phosphate (mirror rG); L-ribouracil-3 '-phosphate (mirror dU).

[00174] In some embodiments, modified ribonucleotides include modified

deoxyribonucleotides, for example 5'OMe DNA (5-methyl-deoxyriboguanosine-3'- phosphate) which may be useful as a nucleotide in the 5' terminal position (position number 1); PACE (deoxyriboadenine 3' phosphonoacetate, deoxyribocytidine 3' phosphonoacetate, deoxyriboguanosine 3' phosphonoacetate, deoxyribothymidine 3' phosphonoacetate.

[00175] Modifications may be present in one or more strands of a nucleic acid molecule disclosed herein, e.g., in the sense strand, the antisense strand, or both strands. In certain embodiments, the antisense strand may include modifications and the sense strand my only include unmodified RNA.

Nucleobases

[00176] Nucleobases of the nucleic acid disclosed herein may include unmodified ribonucleotides (purines and pyrimidines) such as adenine, guanine, cytosine, uridine. The nucleobases in one or both strands can be modified with natural and synthetic nucleobases such as thymine, xanthine, hypoxanthine, inosine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, any "universal base" nucleotides; 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5- trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine,

deazapurines, heterocyclic substituted analogs of purines and pyrimidines, e.g.,

aminoethyoxy phenoxazine, derivatives of purines and pyrimidines (e.g., 1 -alkyl-, 1- alkenyl-, heteroaromatic- and 1-alkynyl derivatives) and tautomers thereof, 8-oxo-N 6 - methyladenine, 7-diazaxanthine, 5-methylcytosine, 5-methyluracil, 5-(l-propynyl)uracil, 5- (1-propynyl) cytosine and 4,4-ethanocytosine). Other examples of suitable bases include non-purinyl and non-pyrimidinyl bases such as 2-aminopyridine and triazines.

Sugar moieties

[00177] Sugar moieties in nucleic acid disclosed herein may include 2'-hydroxyl- pentofuranosyl sugar moiety without any modification. Alternatively, sugar moieties can be modified such as, 2'-deoxy-pentofuranosyl sugar moiety, D-ribose, hexose, modification at the 2' position of the pentofuranosyl sugar moiety such as 2'-0-alkyl (including 2'-0- methyl and 2'-0-ethyl), i.e., 2'-alkoxy, 2'-amino, 2'-0-allyl, 2'-S-alkyl, 2'-halogen

(including 2'-fluoro, chloro, and bromo), 2'-methoxyethoxy, 2'-0-methoxyethyl, 2' -0-2- methoxyethyl, 2'-allyloxy (-OCH 2 CH=CH 2 ), 2'-propargyl, 2'-propyl, ethynyl, propenyl, CF, cyano, imidazole, carboxylate, thioate, Ci to C 10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl, OCF 3 , OCN, 0-, S-, or N- alkyl; 0-, S, or N-alkenyl; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 , N 3 ; heterozycloalkyl; heterozycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl, as, among others, for example as described in European patents EP 0 586 520 Bl or EP 0 618 925 Bl .

[00178] Alkyl group includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., Ci- C for straight chain, C3-C6 for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term Ci-C 6 includes alkyl groups containing 1 to 6 carbon atoms. The alkyl group can be substituted alkyl group such as alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,

aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,

aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[00179] Alkoxy group includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,

arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino

(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,

dichloromethoxy, trichloromethoxy, etc. [00180] In some embodiments, the pentafuronosyl ring may be replaced with acyclic derivatives lacking the C2'-C3'-bond of the pentafuronosyl ring. For example,

acyclonucleotides may substitute a 2-hydroxyethoxymethyl group for-the 2'- deoxyribofuranosyl sugar normally present in dNMPs.

[00181] Halogens include fluorine, bromine, chlorine, iodine.

Backbone

[00182] The nucleoside subunits of the nucleic acid disclosed herein may be linked to each other by phosphodiester bond. The phosphodiester bond may be optionally substituted with other linkages. For example, phosphorothioate, thiophosphate-D-ribose entities, triester, thioate, 2'-5' bridged backbone (may also be referred to as 5'-2'), PACE, 3'-(or -5')deoxy- 3'-(or -5')thio-phosphorothioate, phosphorodithioate, phosphoroselenates, 3 '-(or -5')deoxy phosphinates, borano phosphates, 3 '-(or -5')deoxy-3 '-(or 5'-)amino phosphoramidates, hydrogen phosphonates, phosphonates, borano phosphate esters, phosphoramidates, alkyl or aryl phosphonates and phosphotriester modifications such as alkylphosphotriesters, phosphotriester phosphorus linkages, 5'-ethoxyphosphodiester, P-alkyloxyphosphotriester, methylphosphonate, and nonphosphorus containing linkages for example, carbonate, carbamate, silyl, sulfur, sulfonate, sulfonamide, formacetal, thioformacetyl, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino linkages.

[00183] Nucleic acid molecules disclosed herein may include a peptide nucleic acid (PNA) backbone. The PNA backbone is includes repeating N-(2-aminoethyl)-glycine units linked by peptide bonds. The various bases such as purine, pyrimidine, natural and synthetic bases are linked to the backbone by methylene carbonyl bonds.

Terminal Phosphates

[00184] Modifications can be made at terminal phosphate groups. Non-limiting examples of different stabilization chemistries can be used, e.g., to stabilize the 3 '-end of nucleic acid sequences, including (1) [3-3'] -inverted deoxyribose; (2) deoxyribonucleotide; (3) [5 '-3']- 3'-deoxyribonucleotide; (4) [5 '-3 '] -ribonucleotide; (5) [5 '-3 '] -3 '-O-methyl ribonucleotide; (6) 3 '-glyceryl; (7) [3 '-5 ']-3 '-deoxyribonucleotide; (8) [3 '-3'] -deoxyribonucleotide; (9) [5'- 2']-deoxyribonucleotide; and (10) [5-3']-dideoxyribonucleotide. In addition to unmodified backbone chemistries can be combined with one or more different backbone modifications described herein.

Exemplary chemically modified terminal phosphate groups include those shown below:

ft,

s O

„ ? - !! _ li

o— p— o- o— p— o o-p— o-

I

Sulfonic acid equivalent or Vanadyl equivalent with any combination of other

modifications herein

Conjugates

[00185] Modified nucleotides and nucleic acid molecules (e.g., siNA molecules) as provided herein may include conjugates, for example, a conjugate covalently attached to the chemically-modified nucleic acid molecule. Non-limiting examples of conjugates include conjugates and ligands described in Vargeese et al, U.S. Ser. No. 10/427,160. The conjugate may be covalently attached to a nucleic acid molecule (such as an siNA molecule) via a biodegradable linker. The conjugate molecule may be attached at the 3 '-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule.

[00186] The conjugate molecule may be attached at the 5 '-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule. The conjugate molecule may be attached both the 3 '-end and 5 '-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule, or any combination thereof. In one embodiment, a conjugate molecule may include a molecule that facilitates delivery of a chemically-modified nucleic acid molecule into a biological system, such as a cell. In another embodiment, the conjugate molecule attached to the chemically-modified nucleic acid molecule is a polyethylene glycol, human serum albumin, or a ligand for a cellular receptor that can mediate cellular uptake. Examples of specific conjugate molecules contemplated by herein that can be attached to chemically-modified nucleic acid molecules are described in Vargeese et al, U.S. Ser. No. 10/201,394.

Linkers

[00187] A nucleic acid molecule provided herein (e.g., an siNA) molecule may include a nucleotide, non-nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense region of the nucleic acid to the antisense region of the nucleic acid. A nucleotide linker can be a linker of > 2 nucleotides in length, for example about 3, 4, 5, 6, 7, 8, 9, or 10

nucleotides in length. The nucleotide linker can be a nucleic acid aptamer. By "aptamer" or "nucleic acid aptamer" as used herein refers to a nucleic acid molecule that binds

specifically to a target molecule wherein the nucleic acid molecule has sequence that includes a sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule (such as TIMP1 and TIMP2 mPvNA) where the target molecule does not naturally bind to a nucleic acid. For example, the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non- limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art. See e.g., Gold et al; 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. BiotechnoL, 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. BiotechnoL, 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.

[00188] A non-nucleotide linker may include an abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, polyhydrocarbon, or other polymeric compounds (e.g. polyethylene glycols such as those having between 2 and 100 ethylene glycol units). Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res. 1993, 21 :2585 and Biochemistry 1993, 32: 1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al, Nucleosides & Nucleotides 1991, 10:287; Jschke et al, Tetrahedron Lett. 1993, 34:301; Ono et al, Biochemistry 1991, 30:9914; Arnold et al, International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al, International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000.

5' Ends, 3' Ends and Overhangs

[00189] Nucleic acid molecules disclosed herein (e.g., siNA molecules) may be blunt-ended on both sides, have overhangs on both sides or a combination of blunt and overhang ends. Overhangs may occur on either the 5'- or 3'- end of the sense or antisense strand.

[00190] 5'- and/or 3'- ends of double stranded nucleic acid molecules (e.g., siNA) may be blunt ended or have an overhang. The 5 '-end may be blunt ended and the 3 '-end has an overhang in either the sense strand or the antisense strand. In other embodiments, the 3 '-end may be blunt ended and the 5 '-end has an overhang in either the sense strand or the antisense strand. In yet other embodiments, both the 5'- and 3'- end are blunt ended or both the 5'- and 3'- ends have overhangs.

[00191] The 5'- and/or 3 '-end of one or both strands of the nucleic acid may include a free hydroxyl group. The 5'- and/or 3 '-end of any nucleic acid molecule strand may be modified to include a chemical modification. Such modification may stabilize nucleic acid

molecules, e.g., the 3 '-end may have increased stability due to the presence of the nucleic acid molecule modification. Examples of end modifications (e.g., terminal caps) include, but are not limited to, abasic, deoxy abasic, inverted (deoxy) abasic, glyceryl, dinucleotide, acyclic nucleotide, amino, fluoro, chloro, bromo, CN, CF, methoxy, imidazole, carboxylate, thioate, Ci to C 10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl, OCF 3 , OCN, 0-, S-, or N-alkyl; 0-, S-, or N-alkenyl; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 , N 3 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl, as, among others, described in European patents EP 586,520 and EP 618,925 and other modifications disclosed herein.

[00192] Nucleic acid molecules include those with blunt ends, i.e., ends that do not include any overhanging nucleotides. A nucleic acid molecule can include one or more blunt ends. The blunt ended nucleic acid molecule has a number of base pairs equal to the number of nucleotides present in each strand of the nucleic acid molecule. The nucleic acid molecule can include one blunt end, for example where the 5 '-end of the antisense strand and the 3 '- end of the sense strand do not have any overhanging nucleotides. Nucleic acid molecule may include one blunt end, for example where the 3 '-end of the antisense strand and the 5'- end of the sense strand do not have any overhanging nucleotides. A nucleic acid molecule may include two blunt ends, for example where the 3 '-end of the antisense strand and the 5'- end of the sense strand as well as the 5 '-end of the antisense strand and 3 '-end of the sense strand do not have any overhanging nucleotides. Other nucleotides present in a blunt ended nucleic acid molecule can include, for example, mismatches, bulges, loops, or wobble base pairs to modulate the activity of the nucleic acid molecule to mediate R A interference.

[00193] In certain embodiments of the nucleic acid molecules (e.g., siNA molecules) provided herein, at least one end of the molecule has an overhang of at least one nucleotide (for example 1 to 8 overhang nucleotides). For example, one or both strands of a double stranded nucleic acid molecule disclosed herein may have an overhang at the 5 '-end or at the 3 '-end or both. An overhang may be present at either or both the sense strand and antisense strand of the nucleic acid molecule. The length of the overhang may be as little as one nucleotide and as long as 1 to 8 or more nucleotides (e.g., 1, 2, 3, 4, 5, 6, 7 or 8 nucleotides; in some preferred embodiments an overhang is 2, 3, 4, 5, 6, 7 or 8 nucleotides; for example an overhang may be 2 nucleotides. The nucleotide(s) forming the overhang may be include deoxyribonucleotide(s), ribonucleotide(s), natural and non-natural nucleobases or any nucleotide modified in the sugar, base or phosphate group such as disclosed herein. A double stranded nucleic acid molecule may have both 5'- and 3'- overhangs. The overhangs at the 5 '- and 3 '-end may be of different lengths. An overhang may include at least one nucleic acid modification which may be deoxyribonucleotide. One or more deoxyribonucleotides may be at the 5 '-terminal. The 3 '-end of the respective counter-strand of the nucleic acid molecule may not have an overhang, more preferably not a deoxyribonucleotide overhang. The one or more deoxyribonucleotide may be at the 3'- terminal. The 5 '-end of the respective counter-strand of the dsRNA may not have an overhang, more preferably not a deoxyribonucleotide overhang. The overhang in either the 5'- or the 3 '-end of a strand may be 1 to 8 (e.g., about 1, 2, 3, 4, 5, 6, 7 or 8) unpaired nucleotides, preferably, the overhang is 2-3 unpaired nucleotides; more preferably 2 unpaired nucleotides. Nucleic acid molecules may include duplex nucleic acid molecules with overhanging ends of about 1 to about 20 (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1, 15, 16, 17, 18, 19 or 20); preferably 1-8 (e.g., about 1, 2, 3, 4, 5, 6, 7 or 8) nucleotides, for example, about 21 -nucleotide duplexes with about 19 base pairs and 3 '-terminal mononucleotide, dinucleotide, or trinucleotide overhangs. Nucleic acid molecules herein may include duplex nucleic acid molecules with blunt ends, where both ends are blunt, or alternatively, where one of the ends is blunt. Nucleic acid molecules disclosed herein can include one or more blunt ends, i.e. where a blunt end does not have any overhanging nucleotides. In one embodiment, the blunt ended nucleic acid molecule has a number of base pairs equal to the number of nucleotides present in each strand of the nucleic acid molecule. The nucleic acid molecule may include one blunt end, for example where the 5'- end of the antisense strand and the 3 '-end of the sense strand do not have any overhanging nucleotides. The nucleic acid molecule may include one blunt end, for example where the 3 '-end of the antisense strand and the 5 '-end of the sense strand do not have any

overhanging nucleotides. A nucleic acid molecule may include two blunt ends, for example where the 3 '-end of the antisense strand and the 5 '-end of the sense strand as well as the 5'- end of the antisense strand and 3 '-end of the sense strand do not have any overhanging nucleotides. In certain preferred embodiments the nucleic acid compounds are blunt ended. Other nucleotides present in a blunt ended siNA molecule can include, for example, mismatches, bulges, loops, or wobble base pairs to modulate the activity of the nucleic acid molecule to mediate RNA interference.

[00194] In many embodiments one or more, or all, of the overhang nucleotides of a nucleic acid molecule (e.g., a siNA molecule) as described herein includes are modified such as described herein; for example one or more, or all, of the nucleotides may be 2'- deoxyribonucleotides.

Amount, Location and Patterns of Modifications.

[00195] Nucleic acid molecules (e.g., siNA molecules) disclosed herein may include modified nucleotides as a percentage of the total number of nucleotides present in the nucleic acid molecule. As such, a nucleic acid molecule may include about 5% to about 100% modified nucleotides (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% modified nucleotides). The actual percentage of modified nucleotides present in a given nucleic acid molecule will depend on the total number of nucleotides present in the nucleic acid. If the nucleic acid molecule is single stranded, the percent modification can be based upon the total number of nucleotides present in the single stranded nucleic acid molecule. Likewise, if the nucleic acid molecule is double stranded, the percent modification can be based upon the total number of nucleotides present in the sense strand, antisense strand, or both the sense and antisense strands.

[00196] Nucleic acid molecules disclosed herein may include unmodified RNA as a percentage of the total nucleotides in the nucleic acid molecule. As such, a nucleic acid molecule may include about 5% to about 100% modified nucleotides (e.g., about 5%, 10%>, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%) of total nucleotides present in a nucleic acid molecule.

[00197] A nucleic acid molecule (e.g., an siNA molecule) may include a sense strand that includes about 1 to about 5, specifically about 1 , 2, 3, 4, or 5 phosphorothioate

internucleotide linkages, and/or one or more (e.g., about 1 , 2, 3, 4, 5, or more) 2'-deoxy, 2'- O-methyl, 2'-deoxy-2'-fluoro, and/or one or more (e.g., about 1 , 2, 3, 4, 5, or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3 -end, the 5 '-end, or both of the 3 '- and 5 '-ends of the sense strand; and wherein the antisense strand includes about 1 to about 5 or more, specifically about 1 , 2, 3, 4, 5, or more

phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro, and/or one or more (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3 '-end, the 5 '-end, or both of the 3 '- and 5 '-ends of the antisense strand. A nucleic acid molecule may include about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and/or antisense nucleic acid strand are chemically-modified with 2'-deoxy, 2'-0-methyl and/or 2'-deoxy-2'-fluoro nucleotides, with or without about 1 to about 5 or more, for example about 1 , 2, 3, 4, 5, or more phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3 '-end, the 5 '-end, or both of the 3 '- and 5 '-ends, being present in the same or different strand.

[00198] A nucleic acid molecule may include about 1 to about 5 or more (specifically about 1 , 2, 3, 4, 5 or more) phosphorothioate internucleotide linkages in each strand of the nucleic acid molecule. [00199] A nucleic acid molecule may include 2'-5' internucleotide linkages, for example at the 3 '-end, the 5 '-end, or both of the 3'- and 5 '-ends of one or both nucleic acid sequence strands. In addition, the 2 '-5' internucleotide linkage(s) can be present at various other positions within one or both nucleic acid sequence strands, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a pyrimidine nucleotide in one or both strands of the siNA molecule can include a 2 '-5' internucleotide linkage, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a purine nucleotide in one or both strands of the siNA molecule can include a 2 '-5' internucleotide linkage.

[00200] A chemically-modified short interfering nucleic acid (siNA) molecule may include an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2'-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2'-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2'-deoxy purine nucleotides).

[00201] A chemically-modified short interfering nucleic acid (siNA) molecule may include an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2'-0-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-0-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2'-0-methyl purine nucleotides).

[00202] A chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against TIMP1 and TIMP2 inside a cell or

reconstituted in vitro system may include a sense region, wherein one or more pyrimidine nucleotides present in the sense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the sense region are 2'-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2'-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2'-deoxy purine nucleotides), and an antisense region, wherein one or more pyrimidine nucleotides present in the antisense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the antisense region are 2'-0-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-0-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2'-0-methyl purine nucleotides). The sense region and/or the antisense region can have a terminal cap modification, such as any modification, that is optionally present at the 3'-end, the 5'-end, or both of the 3' and 5'-ends of the sense and/or antisense sequence. The sense and/or antisense region can optionally further include a 3 '-terminal nucleotide overhang having about 1 to about 4 (e.g., about 1, 2, 3, or 4) 2'- deoxyribonucleotides. The overhang nucleotides can further include one or more (e.g., about 1, 2, 3, 4 or more) phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate internucleotide linkages. The purine nucleotides in the sense region may alternatively be 2'- O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-0-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2'-0-methyl purine nucleotides) and one or more purine nucleotides present in the antisense region are 2'-0- methyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-0-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2'-0-methyl purine nucleotides). One or more purine nucleotides in the sense region may alternatively be purine ribonucleotides (e.g., wherein all purine nucleotides are purine ribonucleotides or alternately a plurality of purine nucleotides are purine ribonucleotides) and any purine nucleotides present in the antisense region are 2'-0-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-0-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2'-0-methyl purine nucleotides). One or more purine nucleotides in the sense region and/or present in the antisense region may alternatively selected from the group consisting of 2'-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2'-methoxyethyl nucleotides, 4'-thionucleotides, and 2'-0-methyl nucleotides (e.g., wherein all purine nucleotides are selected from the group consisting of 2'-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2'-methoxyethyl nucleotides, 4'-thionucleotides, and 2'-0-methyl nucleotides or alternately a plurality of purine nucleotides are selected from the group consisting of 2'-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2'-methoxyethyl nucleotides, 4'-thionucleotides, and 2'-0-methyl nucleotides).

[00203] In some embodiments, a nucleic acid molecule (e.g., a siNA molecule) as described herein includes a modified nucleotide (for example one modified nucleotide) in the antisense strand; for example in position 6 or position 7 of the antisense strand.

Modification Patterns and Alternating Modifications

[00204] Nucleic acid molecules (e.g., siNA molecules) provided herein may have patterns of modified and unmodified nucleic acids. A pattern of modification of the nucleotides in a contiguous stretch of nucleotides may be a modification contained within a single nucleotide or group of nucleotides that are covalently linked to each other via standard phosphodiester bonds or, at least partially, through phosphorothioate bonds. Accordingly, a "pattern" as contemplated herein, does not necessarily need to involve repeating units, although it may. Examples of modification patterns that may be used in conjunction with the nucleic acid molecules (e.g., siNA molecules) provided herein include those disclosed in Giese, US Patent No. 7,452,987. For example, nucleic acid molecules (e.g., siNA molecules) provided herein include those having modification patters such as, similar to, or the same as, the patterns shown diagrammatically in figure 2 of the Giese US Patent No. 7,452,987.

[00205] A modified nucleotide or group of modified nucleotides may be at the 5 '-end or 3'- end of the sense or antisense strand, a flanking nucleotide or group of nucleotides is arrayed on both sides of the modified nucleotide or group, where the flanking nucleotide or group either is unmodified or does not have the same modification of the preceding nucleotide or group of nucleotides. The flanking nucleotide or group of nucleotides may, however, have a different modification. This sequence of modified nucleotide or group of modified nucleotides, respectively, and unmodified or differently modified nucleotide or group of unmodified or differently modified nucleotides may be repeated one or more times.

[00206] In some patterns, the 5 '-terminal nucleotide of a strand is a modified nucleotide while in other patterns the 5 '-terminal nucleotide of a strand is an unmodified nucleotide. In some patterns, the 5'- end of a strand starts with a group of modified nucleotides while in other patterns, the 5 '-terminal end is an unmodified group of nucleotides. This pattern may be either on the first stretch or the second stretch of the nucleic acid molecule or on both.

[00207] Modified nucleotides of one strand of the nucleic acid molecule may be

complementary in position to the modified or unmodified nucleotides or groups of nucleotides of the other strand.

[00208] There may be a phase shift between modifications or patterns of modifications on one strand relative to the pattern of modification of the other strand such that the modification groups do not overlap. In one instance, the shift is such that the modified group of nucleotides of the sense strand corresponds to the unmodified group of nucleotides of the antisense strand and vice versa.

[00209] There may be a partial shift of the pattern of modification such that the modified groups overlap. The groups of modified nucleotides in any given strand may optionally be the same length, but may be of different lengths. Similarly, groups of unmodified nucleotides in any given strand may optionally be the same length, or of different lengths.

[00210] In some patterns, the second (penultimate) nucleotide at the terminus of the strand, is an unmodified nucleotide or the beginning of group of unmodified nucleotides.

Preferably, this unmodified nucleotide or unmodified group of nucleotides is located at the 5 '-end of the either or both the sense and antisense strands and even more preferably at the terminus of the sense strand. An unmodified nucleotide or unmodified group of nucleotide may be located at the 5 '-end of the sense strand. In a preferred embodiment the pattern consists of alternating single modified and unmodified nucleotides.

[00211] In some double stranded nucleic acid molecules include a 2'-0-methyl modified nucleotide and a non-modified nucleotide, preferably a nucleotide which is not 2'-0-methyl modified, are incorporated on both strands in an alternating fashion, resulting in a pattern of alternating 2'-0-methyl modified nucleotides and nucleotides that are either unmodified or at least do not include a 2'-0-methyl modification. In certain embodiments, the same sequence of 2'-0-methyl modification and non-modification exists on the second strand; in other embodiments the alternating 2'-0-methyl modified nucleotides are only present in the sense strand and are not present in the antisense strand; and in yet other embodiments the alternating 2'-0-methyl modified nucleotides are only present in the sense strand and are not present in the antisense strand. In certain embodiments, there is a phase shift between the two strands such that the 2'-0-methyl modified nucleotide on the first strand base pairs with a non-modified nucleotide(s) on the second strand and vice versa. This particular arrangement, i.e. base pairing of 2'-0-methyl modified and non-modified nucleotide(s) on both strands is particularly preferred in certain embodiments. In certain embodiments, the pattern of alternating 2'-0-methyl modified nucleotides exists throughout the entire nucleic acid molecule; or the entire duplex region. In other embodiments the pattern of alternating 2'-0-methyl modified nucleotides exists only in a portion of the nucleic acid; or the entire duplex region.

[00212] In "phase shift" patterns, it may be preferred if the antisense strand starts with a 2'- O-methyl modified nucleotide at the 5 ' end whereby consequently the second nucleotide is non-modified, the third, fifth, seventh and so on nucleotides are thus again 2'-0-methyl modified whereas the second, fourth, sixth, eighth and the like nucleotides are non-modified nucleotides.

[00213] Exemplary Modification Locations and Patterns

[00214] While exemplary patterns are provided in more detail below, all permutations of patterns with of all possible characteristics of the nucleic acid molecules disclosed herein and those known in the art are contemplated (e.g., characteristics include, but are not limited to, length of sense strand, length of antisense strand, length of duplex region, length of hangover, whether one or both ends of a double stranded nucleic acid molecule is blunt or has an overhang, location of modified nucleic acid, number of modified nucleic acids, types of modifications, whether a double overhang nucleic acid molecule has the same or different number of nucleotides on the overhang of each side, whether a one or more than one type of modification is used in a nucleic acid molecule, and number of contiguous

modified/unmodified nucleotides). With respect to all detailed examples provided below, while the duplex region is shown to be 19 nucleotides, the nucleic acid molecules provided herein can have a duplex region ranging from 1 to 49 nucleotides in length as each strand of a duplex region can independently be 17-49 nucleotides in length Exemplary patterns are provided herein. [00215] Nucleic acid molecules may have a blunt end (when n is 0) on both ends that include a single or contiguous set of modified nucleic acids. The modified nucleic acid may be located at any position along either the sense or antisense strand. Nucleic acid molecules may include a group of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 contiguous modified nucleotides. Modified nucleic acids may make up 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 100% of a nucleic acid strand. Modified nucleic acids of the examples immediately below may be in the sense strand only, the antisense strand only, or in both the sense and antisense strand.

[00216] General nucleic acid patters are shown below where X = sense strand nucleotide in the duplex region; X a = 5 '-overhang nucleotide in the sense strand; Xb = 3 '-overhang nucleotide in the sense strand; Y = antisense strand nucleotide in the duplex region; Y a = 3'- overhang nucleotide in the antisense strand; Y b = 5 '-overhang nucleotide in the antisense strand; and M = a modified nucleotide in the duplex region. Each a and b are independently 0 to 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7 or 8). Each X, Y, a and b are independently modified or unmodified. The sense and antisense strands can are each independently 17-49 nucleotides in length. The examples provided below have a duplex region of 19 nucleotides; however, nucleic acid molecules disclosed herein can have a duplex region anywhere between 17 and 49 nucleotides and where each strand is independently between 17 and 49 nucleotides in length.

5' XaXXXXXXXXXXXXXXXXXXXXb 3' YbYYYYYYYYYYYYYYYYYYYYa

[00217] Further exemplary nucleic acid molecule patterns are shown below where X = unmodified sense strand nucleotides; x = an unmodified overhang nucleotide in the sense strand; Y = unmodified antisense strand nucleotides; y = an unmodified overhang nucleotide in the antisense strand; and M = a modified nucleotide. The sense and antisense strands can are each independently 17-49 nucleotides in length. The examples provided below have a duplex region of 19 nucleotides; however, nucleic acid molecules disclosed herein can have a duplex region anywhere between 17 and 49 nucleotides and where each strand is independently between 17 and 49 nucleotides in length. ' Μ,,ΧΧΧΧΧΧΧΧΧΜΧΧΧΧΧΧΧΧΧΜ,, ' M n YYYYYYYYYYYYYYYYYYYM n ' xxxxxxxxxxxxxxxxxxx ' YYYYYYYYYMYYYYYYYYY ' XXXXXXXXMMXXXXXXXXX ' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXX ' YYYYYYYYMMYYYYYYYYY ' XXXXXXXXXMXXXXXXXXX ' YYYYYYYYYMYYYYYYYYY ' XXXXXMXXXXXXXXXXXXX ' YYYYYYYYYMYYYYYYYYY ' MXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYMYYYYYY ' XXXXXXXXXXXXXXXXXXM ' YYYYYMYYYYYYYYYYYYY ' XXXXXXXXXMXXXXXXXX

' MYYYYYYYYYYYYYYYYY ' XXXXXXXMXXXXXXXXXX

' YYYYYYYYYYYYYYYYYM ' XXXXXXXXXXXXXMXXXX

' MYYYYYYYYYYYYYYYYY 5' MMMMMMMMMMMMMMMMMM

3' MMMMMMMMMMMMMMMMMM

[00218] Nucleic acid molecules may have blunt ends on both ends with alternating modified nucleic acids. The modified nucleic acids may be located at any position along either the sense or antisense strand.

5' MXMXMXMXMXMXMXMXMXM

3' YMYMYMYMYMYMYMYMYMY

5' XMXMXMXMXMXMXMXMXMX

3' MYMYMYMYMYMYMYMYMYM

5' MMXMMXMMXMMXMMXMMXM

3' YMMYMMYMMYMMYMMYMMY

5' XMMXMMXMMXMMXMMXMMX

3' MMYMMYMMYMMYMMYMMYM

5' MMMXMMMXMMMXMMMXMMM

3' YMMMYMMMYMMMYMMMYMM

5' XMMMXMMMXMMMXMMMXMM

3' MMMYMMMYMMMYMMMYMMM

[00219] Nucleic acid molecules with a blunt 5 '-end and 3 '-end overhang end with a single modified nucleic acid.

[00220] Nucleic acid molecules with a 5 '-end overhang and a blunt 3 '-end with a single modified nucleic acid. [00221] Nucleic acid molecules with overhangs on both ends and all overhangs are modified nucleic acids. In the pattern immediately below, M is n number of modified nucleic acids, where n is an integer from 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7 and 8).

XXXXXXXXXXXXXXXXXXXM MYYYYYYYYYYYYYYYYYYY

[00222] Nucleic acid molecules with overhangs on both ends and some overhang

nucleotides are modified nucleotides. In the patterns immediately below, M is n number of modified nucleotides, x is n number of unmodified overhang nucleotides in the sense strand, y is n number of unmodified overhang nucleotides in the antisense strand, where each n is independently an integer from 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7 and 8), and where each overhang is maximum of 20 nucleotides; preferably a maximum of 8 nucleotides (modified and/or unmodified).

5' XXXXXXXXXXXXXXXXXXXM

3' yYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXXMx

3' yYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXXMxM

3' yYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXXMxMx

3' yYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXXMxMxM

3' yYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXXMxMxMx ' yYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMxMxMxM ' yYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMxMxMxMx ' yYYYYYYYYYYYYYYYYYYY ' MXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYy ' xMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYy ' MxMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYy ' xMxMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYy ' MxMxMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYYy ' xMxMxMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYYy ' MxMxMxMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYYy ' xMxMxMxMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYYy ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYM ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMy ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyM ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyMy ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyMyM ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyMyMy ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyMyMyM ' xXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYYMyMyMyMy ' XXXXXXXXXXXXXXXXXXXX

' MYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXX

' yMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXX

' MyMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXx

' yMyMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXx

' MyMyMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXx

' yMyMyMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXx

' MyMyMyMYYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXx

' yMyMyMyMYYYYYYYYYYYYYYYYYYY odified nucleotides at the 3' end of the sense region. ' XXXXXXXXXXXXXXXXXXXM

' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMM

' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMMM ' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMMMM ' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMMMMM ' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMMMMMM ' YYYYYYYYYYYYYYYYYYY

' XXXXXXXXXXXXXXXXXXXMMMMMMMM ' YYYYYYYYYYYYYYYYYYY ' XXXXXXXXXXXXXXXXXXXMMMMMMMM ' YYYYYYYYYYYYYYYYYYY verhang at the 5 ' end of the sense region.

' MXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYY ' MMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYY ' MMMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYY ' MMMMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYY ' MMMMMXXXXXXXXXXXXXXXXXXX

' YYYYYYYYYYYYYYYYYYY ' MMMMMMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYY ' MMMMMMMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYY ' MMMMMMMMXXXXXXXXXXXXXXXXXXX ' YYYYYYYYYYYYYYYYYYY [00225] Overhang at the 3 ' end of the antisense region.

5' xxxxxxxxxxxxxxxxxxx

3' MYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMMMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMMMMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMMMMMYYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' MMMMMMMMYYYYYYYYYYYYYYYYYYY

[00226] Modified nucleotide(s) within the sense region

5' XXXXXXXXXMXXXXXXXXX

3' YYYYYYYYYYYYYYYYYYY

5' XXXXXXXXXXXXXXXXXXX

3' YYYYYYYYYMYYYYYYYYY 5' XXXXXXXXXXXXXXXXXXXMM

3' YYYYYYYYYYYYYYYYYYY

5' xxxxxxxxxxxxxxxxxxx

3' MMYYYYYYYYYYYYYYYYYYY

[00227] Exemplary nucleic acid molecules are provided below with the equivalent general structure in line with the symbols used above. The following duplexes are in accordance with the pattern:

5' XXXXXXXXXXXXXXXXXXXMM

3' MMYYYYYYYYYYYYYYYYYYY

[00228] TIMPl -A siRNA to human, mouse, rat and rhesus TIMPl having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' CCACCUUAUACCAGCGUUATT 3'

3' TTGGUGGAAUAUGGUCGCAAU 5'

[00229] TIMPl -B siRNA to human and rhesus TIMPl having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3'-ends of the sense and antisense strands.

5' CACUGUUGGCUGUGAGGAATT 3'

3' TTGUGACAACCGACACUCCUU 5'

[00230] TIMPl -C siRNA to human, mouse, rat and rhesus TIMPl having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' GGAAUAUCUCAUUGCAGGATT 3'

3' TTCCUUAUAGAGUAACGUCCU 5' [00231] TIMP2-A siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' UGCAGAUGUAGUGAUCAGGTT 3'

3' TTACGUCUACAUCACUAGUCC 5'

[00232] TIMP2-B siRNA to human, rhesus and rabbit TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3'- ends of the sense and antisense strands.

5' G AGG AUC C AGUAUG AG AUCTT 3'

3' TTCUCCUAGGUCAUACUCUAG 5'

[00233] TIMP2-C siRNA to human, mouse, rat, cow, dog and pig TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' GCAGAUAAAGAUGUUCAAATT 3'

3' TTCGUCUAUUUCUACAAGUUU 5'

[00234] TIMP2-D siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' UAUCUCAUUGCAGGAAAGGTT 3'

3' TTAUAGAGUAACGUCCUUUCC 5'

[00235] TIMP2-E siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3 '-ends of the sense and antisense strands.

5' GCACAGUGUUUCCCUGUUUTT 3'

3' TTCGUGUCACAAAGGGACAAA 5'

Nicks and Gaps in Nucleic Acid Strands [00236] Nucleic acid molecules (e.g., siNA molecules) provided herein may have a strand, preferably the sense strand, that is nicked or gapped. As such, nucleic acid molecules may have three or more strand, for example, such as a meroduplex RNA (mdRNA) disclosed in International Patent Application No. PCT/US07/081836. Nucleic acid molecules with a nicked or gapped strand may be between about 1-49 nucleotides, or may be RISC length (e.g., about 15 to 25 nucleotides) or Dicer substrate length (e.g., about 25 to 30 nucleotides) such as disclosed herein.

[00237] Nucleic acid molecules with three or more strands include, for example, an 'A' (antisense) strand, 'SI ' (second) strand, and 'S2' (third) strand in which the 'SI ' and 'S2' strands are complementary to and form base pairs with non-overlapping regions of the 'A' strand (e.g., an mdRNA can have the form of A:S1S2). The SI, S2, or more strands together form what is substantially similar to a sense strand to the 'A' antisense strand. The double- stranded region formed by the annealing of the 'SI ' and 'A' strands is distinct from and non-overlapping with the double-stranded region formed by the annealing of the 'S2' and 'A' strands. An nucleic acid molecule (e.g., an siNA molecule) may be a "gapped" molecule, meaning a "gap" ranging from 0 nucleotides up to about 10 nucleotides (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides). Preferably, the sense strand is gapped. In some embodiments, the A: SI duplex is separated from the A:S2 duplex by a gap resulting from at least one unpaired nucleotide (up to about 10 unpaired nucleotides) in the 'A' strand that is positioned between the A:S1 duplex and the A:S2 duplex and that is distinct from any one or more unpaired nucleotide at the 3'-end of one or more of the 'Α', 'SI ', or 'S2 strands. The A:S1 duplex may be separated from the A:B2 duplex by a gap of zero nucleotides (i.e., a nick in which only a phosphodiester bond between two nucleotides is broken or missing in the polynucleotide molecule) between the A: SI duplex and the A:S2 duplex-which can also be referred to as nicked dsRNA (ndsRNA). For example, A:S1S2 may be include a dsRNA having at least two double-stranded regions that combined total about 14 base pairs to about 40 base pairs and the double-stranded regions are separated by a gap of about 0 to about 10 nucleotides, optionally having blunt ends, or A:S1S2 may include a dsRNA having at least two double-stranded regions separated by a gap of up to 10 nucleotides wherein at least one of the double-stranded regions includes between about 5 base pairs and 13 base pairs. Dicer Substrates

[00238] In certain embodiments, the nucleic acid molecules (e.g., siNA molecules) provided herein may be a precursor "Dicer substrate" molecule, e.g., double stranded nucleic acid, processed in vivo to produce an active nucleic acid molecules, for example as described in Rossi, US Patent App. No. 20050244858. In certain conditions and situations, it has been found that these relatively longer dsRNA siNA species, e.g., of from about 25 to about 30 nucleotides, can give unexpectedly effective results in terms of potency and duration of action. Without wishing to be bound by any particular theory, it is thought that the longer dsRNA species serve as a substrate for the enzyme Dicer in the cytoplasm of a cell. In addition to cleaving double stranded nucleic acid into shorter segments, Dicer may facilitate the incorporation of a single-stranded cleavage product derived from the cleaved dsRNA into the RNA-induced silencing complex (RISC complex) that is responsible for the destruction of the cytoplasmic RNA derived from the target gene.

[00239] Dicer substrates may have certain properties which enhance its processing by Dicer. Dicer substrates are of a length sufficient such that it is processed by Dicer to produce an active nucleic acid molecule and may further include one or more of the following properties: (i) the dsRNA is asymmetric, e.g., has a 3' overhang on the first strand (antisense strand) and (ii) the dsRNA has a modified 3' end on the antisense strand (sense strand) to direct orientation of Dicer binding and processing of the dsRNA to an active siRNA. In certain embodiments, the longest strand in the Dicer substrate may be 24-30 nucleotides.

[00240] Dicer substrates may be symmetric or asymmetric. The Dicer substrate may have a sense strand includes 22-28 nucleotides and the antisense strand may include 24-30 nucleotides; thus, in some embodiments the resulting Dicer substrate may have an overhang on the 3' end of the antisense strand. Dicer substrate may have a sense strand 25 nucleotides in length, and the antisense strand having 27 nucleotides in length with a 2 base 3'- overhang. The overhang may be 1-3 nucleotides, for example 2 nucleotides. The sense strand may also have a 5' phosphate.

[00241] An asymmetric Dicer substrate may further contain two deoxyribonucleotides at the 3 '-end of the sense strand in place of two of the ribonucleotides. Some exemplary Dicer substrates lengths and structures are 21+0, 21+2, 21-2, 22+0, 22+1, 22-1, 23+0, 23+2, 23-2, 24+0, 24+2, 24-2, 25+0, 25+2, 25-2, 26+0, 26+2, 26-2, 27+0, 27+2, and 27-2.

[00242] The sense strand of a Dicer substrate may be between about 22 to about 30 (e.g., about 22, 23, 24, 25, 26, 27, 28, 29 or 30); about 22 to about 28; about 24 to about 30; about 25 to about 30; about 26 to about 30; about 26 and 29; or about 27 to about 28 nucleotides in length. In certain preferred embodiments Dicer substrates contain sense and antisense strands, that are at least about 25 nucleotides in length and no longer than about 30 nucleotides; between about 26 and 29 nucleotides; or 27 nucleotides in length. The sense and antisense strands may be the same length (blunt ended), different lengths (have overhangs), or a combination. The sense and antisense strands may exist on the same polynucleotide or on different polynucleotides. A Dicer substrate may have a duplex region of about 19, 20, 21, 22, 23, 24, 25 or 27 nucleotides.

[00243] Like other siNA molecules provided herein, the antisense strand of a Dicer substrate may have any sequence that anneals to the antisense strand under biological conditions, such as within the cytoplasm of a eukaryotic cell.

[00244] Dicer substrates may have any modifications to the nucleotide base, sugar or phosphate backbone as known in the art and/or as described herein for other nucleic acid molecules (such as siNA molecules). In certain embodiments, Dicer substrates may have a sense strand is modified for Dicer processing by suitable modifiers located at the 3 ' end of the sense strand, i.e., the dsRNA is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2- hydroxyethoxymethyl group for-the 2'-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotides modifiers that could be used in Dicer substrate siNA molecules include 3'-deoxyadenosine (cordycepin), 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxyinosine (ddl), 2',3'-dideoxy-3'-thiacytidine (3TC), 2',3'-didehydro-2',3'- dideoxythymidi- ne (d4T) and the monophosphate nucleotides of 3'-azido-3'- deoxythymidine (AZT), 2',3'-dideoxy-3 '-thiacytidine (3TC) and 2',3'-didehydro-2',3'-dide- oxythymidine (d4T). In one embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, they may replace ribonucleotides (e.g., 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3' end of the sense strand) such that the length of the Dicer substrate does not change.

When sterically hindered molecules are utilized, they may be attached to the ribonucleotide at the 3 ' end of the antisense strand. Thus, in certain embodiments the length of the strand does not change with the incorporation of the modifiers. In certain embodiments, two DNA bases in the dsRNA are substituted to direct the orientation of Dicer processing of the antisense strand. In a further embodiment of, two terminal DNA bases are substituted for two ribonucleotides on the 3 '-end of the sense strand forming a blunt end of the duplex on the 3 ' end of the sense strand and the 5 ' end of the antisense strand, and a two-nucleotide RNA overhang is located on the 3 '-end of the antisense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

[00245] In certain embodiments modifications are included in the Dicer substrate such that the modification does not prevent the nucleic acid molecule from serving as a substrate for Dicer. In one embodiment, one or more modifications are made that enhance Dicer processing of the Dicer substrate. One or more modifications may be made that result in more effective RNAi generation. One or more modifications may be made that support a greater RNAi effect. One or more modifications are made that result in greater potency per each Dicer substrate to be delivered to the cell. Modifications may be incorporated in the 3 '-terminal region, the 5 '-terminal region, in both the 3 '-terminal and 5 '-terminal region or at various positions within the sequence. Any number and combination of modifications can be incorporated into the Dicer substrate so long as the modification does not prevent the nucleic acid molecule from serving as a substrate for Dicer. Where multiple modifications are present, they may be the same or different. Modifications to bases, sugar moieties, the phosphate backbone, and their combinations are contemplated. Either 5 '-terminus can be phosphorylated.

[00246] Examples of Dicer substrate phosphate backbone modifications include

phosphonates, including methylphosphonate, phosphorothioate, and phosphotriester modifications such as alkylphosphotriesters, and the like. Examples of Dicer substrate sugar moiety modifications include 2'-alkyl pyrimidine, such as 2'-0-methyl, 2'-fluoro, amino, and deoxy modifications and the like (see, e.g., Amarzguioui et al, 2003). Examples of Dicer substrate base group modifications include abasic sugars, 2-O-alkyl modified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and 5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's, could also be incorporated.

[00247] The sense strand may be modified for Dicer processing by suitable modifiers located at the 3' end of the sense strand, i.e., the Dicer substrate is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for-the 2'-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotides modifiers could include 3'-deoxyadenosine

(cordycepin), 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'- dideoxy-3'-thiacytidine (3TC), 2',3'-didehydro-2',3'-dideoxythymidi- ne (d4T) and the monophosphate nucleotides of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxy-3'- thiacytidine (3TC) and 2',3'-didehydro-2',3'-dide-oxythymidine (d4T). In one

embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3 ' end of the sense strand. When sterically hindered molecules are utilized, they are attached to the ribonucleotide at the 3 ' end of the antisense strand. Thus, the length of the strand does not change with the incorporation of the modifiers. In another embodiment, substituting two DNA bases in the Dicer substrate to direct the orientation of Dicer processing of the antisense strand is contemplated. In a further embodiment of the present invention, two terminal DNA bases are substituted for two ribonucleotides on the 3'- end of the sense strand forming a blunt end of the duplex on the 3' end of the sense strand and the 5 ' end of the antisense strand, and a two-nucleotide RNA overhang is located on the 3 '-end of the antisense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

[00248] The antisense strand may be modified for Dicer processing by suitable modifiers located at the 3' end of the antisense strand, i.e., the dsRNA is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as

deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the 2'-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotide modifiers could include 3'-deoxyadenosine

(cordycepin), 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'- dideoxy-3'-thiacytidine (3TC), 2',3'-didehydro-2',3'-dideoxythymidi- ne (d4T) and the monophosphate nucleotides of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxy-3'- thiacytidine (3TC) and 2',3'-didehydro-2',3'-dide- oxythymidine (d4T). In one

embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3 ' end of the antisense strand. When sterically hindered molecules are utilized, they are attached to the ribonucleotide at the 3 ' end of the antisense strand. Thus, the length of the strand does not change with the incorporation of the modifiers. In another embodiment, the two DNA bases in the dsRNA may be substituted to direct the orientation of Dicer processing. In a further embodiment, two terminal DNA bases are located on the 3' end of the antisense strand in place of two ribonucleotides forming a blunt end of the duplex on the 5 ' end of the sense strand and the 3 ' end of the antisense strand, and a two-nucleotide R A overhang is located on the 3 '-end of the sense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

[00249] Dicer substrates with a sense and an antisense strand can be linked by a third structure. The third structure will not block Dicer activity on the Dicer substrate and will not interfere with the directed destruction of the RNA transcribed from the target gene. The third structure may be a chemical linking group. Suitable chemical linking groups are known in the art and can be used. Alternatively, the third structure may be an

oligonucleotide that links the two oligonucleotides of the dsRNA is a manner such that a hairpin structure is produced upon annealing of the two oligonucleotides making up the Dicer substrate. The hairpin structure preferably does not block Dicer activity on the Dicer substrate or interfere with the directed destruction of the RNA transcribed from the target gene.

[00250] The sense and antisense strands of the Dicer substrate are not required to be completely complementary. They only need to be substantially complementary to anneal under biological conditions and to provide a substrate for Dicer that produces an siRNA sufficiently complementary to the target sequence. [00251] Dicer substrate can have certain properties that enhance its processing by Dicer. The Dicer substrate can have a length sufficient such that it is processed by Dicer to produce an active nucleic acid molecules (e.g., siR A) and may have one or more of the following properties: (i) the Dicer substrate is asymmetric, e.g., has a 3' overhang on the first strand (antisense strand) and (ii) the Dicer substrate has a modified 3' end on the second strand (sense strand) to direct orientation of Dicer binding and processing of the Dicer substrate to an active siRNA. The Dicer substrate can be asymmetric such that the sense strand includes 22-28 nucleotides and the antisense strand includes 24-30 nucleotides. Thus, the resulting Dicer substrate has an overhang on the 3' end of the antisense strand. The overhang is 1-3 nucleotides, for example 2 nucleotides. The sense strand may also have a 5' phosphate.

[00252] A Dicer substrate may have an overhang on the 3 ' end of the antisense strand and the sense strand is modified for Dicer processing. The 5' end of the sense strand may have a phosphate. The sense and antisense strands may anneal under biological conditions, such as the conditions found in the cytoplasm of a cell. A region of one of the strands, particularly the antisense strand, of the Dicer substrate may have a sequence length of at least 19 nucleotides, wherein these nucleotides are in the 21 -nucleotide region adjacent to the 3' end of the antisense strand and are sufficiently complementary to a nucleotide sequence of the RNA produced from the target gene. A Dicer substrate may also have one or more of the following additional properties: (a) the antisense strand has a right shift from a

corresponding 21-mer (i.e., the antisense strand includes nucleotides on the right side of the molecule when compared to the corresponding 21-mer), (b) the strands may not be completely complementary, i.e., the strands may contain simple mismatch pairings and (c) base modifications such as locked nucleic acid(s) may be included in the 5' end of the sense strand.

[00253] An antisense strand of a Dicer substrate nucleic acid molecule may be modified to include 1-9 ribonucleotides on the 5' -end to give a length of 22-28 nucleotides. When the antisense strand has a length of 21 nucleotides, then 1-7 ribonucleotides, or 2-5

ribonucleotides and or 4 ribonucleotides may be added on the 3 '-end. The added ribonucleotides may have any sequence. Although the added ribonucleotides may be complementary to the target gene sequence, full complementarity between the target sequence and the antisense strands is not required. That is, the resultant antisense strand is sufficiently complementary with the target sequence. A sense strand may then have 24-30 nucleotides. The sense strand may be substantially complementary with the antisense strand to anneal to the antisense strand under biological conditions. In one embodiment, the antisense strand may be synthesized to contain a modified 3' -end to direct Dicer processing. The sense strand may have a 3' overhang. The antisense strand may be synthesized to contain a modified 3 ' -end for Dicer binding and processing and the sense strand has a 3 ' overhang.

TIMP1 and TIMP2

[00254] Exemplary nucleic acid sequence of target tissue inhibitors of metalloproteinase-1 and -2 (human TIMP1 and TIMP2) cDNA is disclosed in GenBank accession numbers: NM_003454 and NM_003455 and the corresponding m NA sequence, for example as listed as SEQ ID NO: 1 and SEQ ID NO:2. One of ordinary skill in the art would understand that a given sequence may change over time and to incorporate any changes needed in the nucleic acid molecules herein accordingly.

[00255] Expression of TIMP1 and TIMP2 was shown to be increased in fibrotic liver from rats with hepatic fibrosis (Nie, et al 2004. World J. Gastroenterol. 10:86-90). TIMP1 and TIMP2 are potential targets for the treatment of fibrosis.

Methods and Compositions for Inhibiting TIMP1 and TIMP2

[00256] Provided are compositions and methods for inhibition of TIMP1 and TIMP2 expression by using small nucleic acid molecules, such as short interfering nucleic acid (siNA), interfering RNA (RNAi), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating or that mediate RNA interference against TIMP1 and TIMP2 gene expression. The composition and methods disclosed herein are also useful in treating various fibrosis such as liver fibrosis, lung fibrosis, kidney fibrosis and fibrotic conditions shown in Table I, supra.

[00257] Nucleic acid molecule(s) and/or methods as disclosed herein may be used to down regulate the expression of gene(s) that encode RNA referred to, by example, Genbank Accession NM 003254.2 and NM 004255.4. [00258] Compositions, methods and kits provided herein may include one or more nucleic acid molecules (e.g., siNA) and methods that independently or in combination modulate (e.g., downregulate) the expression of TIMPland or TIMP2 protein and/or genes encoding TIMPl and TIMP2 proteins, proteins and/or genes encoding TIMPl and TIMP2 associated with the maintenance and/or development of diseases, conditions or disorders associated with TIMPl and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis (e.g., genes encoding sequences comprising those sequences referred to by GenBank Accession Nos. NM-003254 and NM_003255), or a TIMPl and TIMP2 gene family member where the genes or gene family sequences share sequence homology. The description of the various aspects and embodiments is provided with reference to exemplary genes TIMPl and TIMP2. However, the various aspects and embodiments are also directed to other related TIMPl and TIMP2 genes, such as homo log genes and transcript variants, and

polymorphisms (e.g., single nucleotide polymorphism, (SNPs)) associated with certain TIMPl and TIMP2 genes. As such, the various aspects and embodiments are also directed to other genes that are involved in TIMPl and TIMP2 mediated pathways of signal transduction or gene expression that are involved, for example, in the maintenance or development of diseases, traits, or conditions described herein. These additional genes can be analyzed for target sites using the methods described for the TIMPl and TIMP2 gene herein. Thus, the modulation of other genes and the effects of such modulation of the other genes can be performed, determined, and measured as described herein.

[00259] In one embodiment, compositions and methods provided herein include a double- stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a TIMPl and TIMP2 gene (e.g., human TIMPl and TIMP2 exemplified by SEQ ID NO: l and SEQ ID NO:2, respectively), where the nucleic acid molecule includes about 15 to about 49 base pairs.

[00260] In one embodiment, a nucleic acid disclosed may be used to inhibit the expression of the TIMPl and TIMP2 gene or a TIMPl and TIMP2 gene family where the genes or gene family sequences share sequence homology. Such homologous sequences can be identified as is known in the art, for example using sequence alignments. Nucleic acid molecules can be designed to target such homologous sequences, for example using perfectly complementary sequences or by incorporating non-canonical base pairs, for example mismatches and/or wobble base pairs, that can provide additional target sequences. In instances where mismatches are identified, non-canonical base pairs (for example, mismatches and/or wobble bases) can be used to generate nucleic acid molecules that target more than one gene sequence. In a non-limiting example, non-canonical base pairs such as UU and CC base pairs are used to generate nucleic acid molecules that are capable of targeting sequences for differing TIMP1 and TIMP2 targets that share sequence homology. As such, one advantage of using siNAs disclosed herein is that a single nucleic acid can be designed to include nucleic acid sequence that is complementary to the nucleotide sequence that is conserved between the homologous genes. In this approach, a single nucleic acid can be used to inhibit expression of more than one gene instead of using more than one nucleic acid molecule to target the different genes.

[00261] Nucleic acid molecules may be used to target conserved sequences corresponding to a gene family or gene families such as TIMP1 and TIMP2 family genes. As such, nucleic acid molecules targeting multiple TIMP1 and TIMP2 targets can provide increased therapeutic effect. In addition, nucleic acid can be used to characterize pathways of gene function in a variety of applications. For example, nucleic acid molecules can be used to inhibit the activity of target gene(s) in a pathway to determine the function of

uncharacterized gene(s) in gene function analysis, mRNA function analysis, or translational analysis. The nucleic acid molecules can be used to determine potential target gene pathways involved in various diseases and conditions toward pharmaceutical development. The nucleic acid molecules can be used to understand pathways of gene expression involved in, for example fibroses such as liver, kidney or pulmonary fibrosis, and/or inflammatory and proliferative traits, diseases, disorders, and/or conditions.

[00262] In one embodiment, the compositions and methods provided herein include a nucleic acid molecule having RNAi activity against TIMP1 RNA, where the nucleic acid molecule includes a sequence complementary to any RNA having TIMP1 encoding sequence. In another embodiment, a nucleic acid molecule may have RNAi activity against TIMP1 RNA, where the nucleic acid molecule includes a sequence complementary to an RNA having variant TIMP1 encoding sequence, for example other mutant TIMP1 genes known in the art to be associated with the maintenance and/or development of fibrosis. In another embodiment, a nucleic acid molecule disclosed herein includes a nucleotide sequence that can interact with nucleotide sequence of a TIMP1 gene and thereby mediate silencing of TIMP1 gene expression, for example, wherein the nucleic acid molecule mediates regulation of TIMP1 gene expression by cellular processes that modulate the chromatin structure or methylation patterns of the TIMP1 gene and prevent transcription of the TIMP1 gene.

[00263] In another embodiment the comporsitions and methods provided herein include a nucleic acid molecule having RNAi activity against TIMP2 R A, where the nucleic acid molecule includes a sequence complementary to any RNA having TIMP2 encoding sequence, such as those sequences having GenBank Accession No. NM_003455. Nucleic acid molecules may have RNAi activity against TIMP2 RNA, where the nucleic acid molecule includes a sequence complementary to an RNA having variant TIMP2 encoding sequence, for example other mutant TIMP2 genes known in the art to be associated with the maintenance and/or development of fibrosis. Nucleic acid molecules disclosed herein include a nucleotide sequence that can interact with nucleotide sequence of a TIMP2 gene and thereby mediate silencing of TIMP1 gene expression, e.g., where the nucleic acid molecule mediates regulation of TIMP2 gene expression by cellular processes that modulate the chromatin structure or methylation patterns of the TIMP2 gene and prevent transcription of the TIMP2 gene.

Methods of Treatment

[00264] In one embodiment, nucleic acid molecules may be used to down regulate or inhibit the expression of TIMP1 and/or TIMP1 proteins arising from TIMP1 and/or TIMP1 haplotype polymorphisms that are associated with a disease or condition, (e.g., fibrosis). Analysis of TIMP1 and/or TIMP1 genes, or TIMP1 and/or TIMP1 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with nucleic acid molecules disclosed herein and any other composition useful in treating diseases related to TIMP1 and/or TIMP1 gene expression. As such, analysis of TIMP1 and/or TIMP1 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of TIMP1 and/or TIMP1 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain TIMP1 and/or TIMP1 proteins associated with a trait, condition, or disease.

[00265] In one embodiment, nucleic acid molecules may be used to down regulate or inhibit the expression of TIMP2 and/or TIMP2 proteins arising from TIMP2 and/or TIMP2 haplotype polymorphisms that are associated with a disease or condition, (e.g., fibrosis). Analysis of TIMP2 and/or TIMP2 genes, or TIMP2 and/or TIMP2 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with nucleic acid molecules disclosed herein and any other composition useful in treating diseases related to TIMP2 and/or TIMP2 gene expression. As such, analysis of TIMP2 and/or TIMP2 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of TIMP2 and/or TIMP2 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain TIMP2 and/or TIMP2 proteins associated with a trait, condition, or disease.

[00266] Provided are compositions and methods for inhibition of TIMP1 and TIMP2 expression by using small nucleic acid molecules as provided herein, such as short interfering nucleic acid (siNA), interfering RNA (RNAi), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating or that mediate RNA interference against TIMP1 and TIMP2 gene expression. The composition and methods disclosed herein are also useful in treating various fibrosis such as liver fibrosis, lung fibrosis, and kidney fibrosis.

[00267] The nucleic acid molecules disclosed herein individually, or in combination or in conjunction with other drugs, can be use for preventing or treating diseases, traits, conditions and/or disorders associated with TIMP1 and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis. [00268] The nucleic acid molecules disclosed herein are able to inhibit the expression of TIMP1 or TIMP2 in a sequence specific manner. The nucleic acid molecules may include a sense strand and an antisense strand which include contiguous nucleotides that are at least partially complementary (antisense) to a TIMP1 or TIMP2 mR A.

[00269] In some embodiments, dsR A specific for TIMP1 or TIMP2 can be used in conjunction with other dsRNA specific for other molecular chaperones that assist in the folding of newly synthesized proteins such as, calnexin, calreticulin, BiP (Bergeron et al. Trends Biochem. Sci. 1994; 19: 124-128; Herbert et al. 1995; Cold Spring Harb. Symp. Quant. Biol. 60:405-415)

[00270] Fibrosis can be treated by R A interference using nucleic acid molecules as disclosed herein. Exemplary fibrosis include liver fibrosis, peritoneal fibrosis, lung fibrosis, kidney fibrosis, vocal cord fibrosis, intestinal fibrosis. The nucleic acid molecules disclosed herein may inhibit the expression of TIMP1 or TIMP2 in a sequence specific manner.

[00271] Treatment of fibrosis can be monitored by determining the level of extracellular collagen using suitable techniques known in the art such as, using anti-collagen I antibodies. Treatment can also be monitored by determining the level of TIMP1 or TIMP2 mRNA or the level of TIMP1 or TIMP2 protein in the cells of the affected tissue. Treatment can also be monitored by non-invasive scanning of the affected organ or tissue such as by computer assisted tomography scan, magnetic resonance elastography scans.

[00272] A method for treating or preventing TIMP1 associated disease or condition in a subject or organism may include contacting the subject or organism with a nucleic acid molecule as provided herein under conditions suitable to modulate the expression of the TIMP1 gene in the subject or organism.

[00273] A method for treating or preventing TIMP2 associated disease or condition in a subject or organism may include contacting the subject or organism with a nucleic acid molecule as provided herein under conditions suitable to modulate the expression of the TIMP2 gene in the subject or organism. [00274] A method for treating or preventing fibrosis in a subject or organism may include contacting the subject or organism with a nucleic acid molecule under conditions suitable to modulate the expression of the TIMP1 and/or TIMP2 gene in the subject or organism.

[00275] A method for treating or preventing one or more fibroses selected from the group consisting of liver fibrosis, kidney fibrosis, and pulmonary fibrosis in a subject or organism may include contacting the subject or organism with a nucleic acid molecule under conditions suitable to modulate the expression of the TIMP1 and/or TIMP2 gene in the subject or organism.

FIBROTIC DISEASES

[00276] Fibrotic diseases are generally characterized by the excess deposition of a fibrous material within the extracellular matrix, which contributes to abnormal changes in tissue architecture and interferes with normal organ function.

[00277] All tissues damaged by trauma respond by the initiation of a wound-healing program. Fibrosis, a type of disorder characterized by excessive scarring, occurs when the normal self-limiting process of wound healing response is disturbed, and causes excessive production and deposition of collagen. As a result, normal organ tissue is replaced with scar tissue, which eventually leads to the functional failure of the organ.

[00278] Fibrosis may be initiated by diverse causes and in various organs. Liver cirrhosis, pulmonary fibrosis, sarcoidosis, keloids and kidney fibrosis are all chronic conditions associated with progressive fibrosis, thereby causing a continuous loss of normal tissue function.

[00279] Acute fibrosis (usually with a sudden and severe onset and of short duration) occurs as a common response to various forms of trauma including accidental injuries (particularly injuries to the spine and central nervous system), infections, surgery, ischemic illness (e.g. cardiac scarring following heart attack), burns, environmental pollutants, alcohol and other types of toxins, acute respiratory distress syndrome, radiation and chemotherapy

treatments).

[00280] Fibrosis, a fibrosis related pathology or a pathology related to aberrant crosslinking of cellular proteins may all be treated by the siRNAs disclosed herein. Fibrotic diseases or diseases in which fibrosis is evident (fibrosis related pathology) include both acute and chronic forms of fibrosis of organs, including all etiological variants of the following:

pulmonary fibrosis, including interstitial lung disease and fibrotic lung disease, liver fibrosis, cardiac fibrosis including myocardial fibrosis, kidney fibrosis including chronic renal failure, skin fibrosis including scleroderma, keloids and hypertrophic scars;

myelofibrosis (bone marrow fibrosis); fibrosis in the brain associated with bain infarction; all types of ocular scarring including proliferative vitreoretinopathy (PVR) and scarring resulting from surgery to treat cataract or glaucoma; inflammatory bowel disease of variable etiology, macular degeneration, Grave's ophthalmopathy, drug induced ergotism, keloid scars, scleroderma, psoriasis, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myleoid leukemia, acute myelogenous leukemia, myelodysplasia syndrome,

myeloproferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, fibrosis associated with brain infarction and collagenous colitis .

[00281] In various embodiments, the compounds (nucleic acid molecules) as disclosed herein may be used to treat fibrotic diseases, for example as disclosed herein, as well as many other diseases and conditions apart from fibrotic diseases, for example such as disclosed herein. Other conditions to be treated include fibrotic diseases in other organs - kidney fibrosis for any reason (CKD including ESRD); lung fibrosis (including ILF);

myelofibrosis, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma; cardiofibrosis, failure of glaucoma filtering operation; intestinal adhesions.

Ocular surgery and fibrotic complications

[00282] Contracture of scar tissue resulting from eye surgery may often occur. Glaucoma surgery to create new drainage channels often fails due to scarring and contraction of tissues and the generated drainage system may be blocked requiring additional surgical

intervention. Current anti-scarring regimens (Mitomycin C or 5FU) are limited due to the complications involved (e.g. blindness) e.g. see Cordeiro MF, et al, Human anti- transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent Invest Ophthalmol Vis Sci. 1999 Sep;40(10):2225-34. There may also be contraction of scar tissue formed after corneal trauma or corneal surgery, for example laser or surgical treatment for myopia or refractive error in which contraction of tissues may lead to inaccurate results. Scar tissue may be formed on/in the vitreous humor or the retina, for example, and may eventually causes blindness in some diabetics, and may be formed after detachment surgery, called proliferative vitreoretinopathy (PVR). PVR is the most common complication following retinal detachment and is associated with a retinal hole or break. PVR refers to the growth of cellular membranes within the vitreous cavity and on the front and back surfaces of the retina containing retinal pigment epithelial (RPE) cells. These membranes, which are essentially scar tissues, exert traction on the retina and may result in recurrences of retinal detachment, even after an initially successful retinal detachment procedure.

[00283] Scar tissue may be formed in the orbit or on eye and eyelid muscles after squint, orbital or eyelid surgery, or thyroid eye disease, and where scarring of the conjunctiva occurs as may happen after glaucoma surgery or in cicatricial disease, inflammatory disease, for example, pemphigoid, or infective disease, for example, trachoma. A further eye problem associated with the contraction of collagen-including tissues is the opacification and contracture of the lens capsule after cataract extraction. Important role for MMPs has been recognized in ocular diseases including wound healing, dry eye, sterile corneal ulceration, recurrent epithelial erosion, corneal neovascularization, pterygium,

conjuctivochalasis, glaucoma, PVR, and ocular fibrosis.

Liver fibrosis

[00284] Liver fibrosis (LF) is a generally irreversible consequence of hepatic damage of several etiologies. In the Western world, the main etiologic categories are: alcoholic liver disease (30-50%), viral hepatitis (30%>), biliary disease (5-10%), primary hemochromatosis (5%>), and drug-related and cryptogenic cirrhosis of, unknown etiology, (10-15%). Wilson's disease, i -antitrypsin deficiency and other rare diseases also have liver fibrosis as one of the symptoms. Liver cirrhosis, the end stage of liver fibrosis, frequently requires liver transplantation and is among the top ten causes of death in the Western world.

Kidney fibrosis and related conditions.

Chronic Renal Failure (CRF)

[00285] Chronic renal failure is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. CRF is slowly progressive. It most often results from any disease that causes gradual loss of kidney function, and fibrosis is the main pathology that produces CRF.

Diabetic nephropathy

[00286] Diabetic nephropathy, hallmarks of which are glomerulosclerosis and

tubulointerstitial fibrosis, is the single most prevalent cause of end-stage renal disease in the modern world, and diabetic patients constitute the largest population on dialysis. Such therapy is costly and far from optimal. Transplantation offers a better outcome but suffers from a severe shortage of donors.

Chronic Kidney Disease

[00287] Chronic kidney disease (CKD) is a worldwide public health problem and is recognized as a common condition that is associated with an increased risk of cardiovascular disease and chronic renal failure (CRF).

[00288] The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased kidney glomerular filtration rate (GFR) for three or more months. Other markers of CKD are also known and used for diagnosis. In general, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. Recently, the K DOQI published a classification of the stages of CKD, as follows:

Stage 1 : Kidney damage with normal or increased GFR (>90 mL/min/1.73 ml) Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 ml)

Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)

Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis)

[00289] In stages 1 and 2 CKD, GFR alone does not confirm the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests, may be relied upon. Pathophysiology of CKD

[00290] Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. Irrespective of the etiology of renal injury, with progressive destruction of nephrons, the kidney is able to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes so that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will approximately double with a 50% reduction in GFR. Therefore, a doubling in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient actually represents a loss of 50%) of functioning nephron mass.

[00291] The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons noted, is thought to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop lesions that are identical to those observed in humans with CKD.

[00292] The two most common causes of chronic kidney disease are diabetes and hypertension. Other factors include acute insults from nephrotoxins, including contrasting agents, or decreased perfusion; Proteinuria; Increased renal ammoniagenesis with interstitial injury; Hyperlipidemia; Hyperphosphatemia with calcium phosphate deposition; Decreased levels of nitrous oxide and smoking.

[00293] In the United States, the incidence and prevalence of CKD is rising, with poor outcomes and high cost to the health system. Kidney disease is the ninth leading cause of death in the US. The high rate of mortality has led the US Surgeon General's mandate for America's citizenry, Healthy People 2010, to contain a chapter focused on CKD. The objectives of this chapter are to articulate goals and to provide strategies to reduce the incidence, morbidity, mortality, and health costs of chronic kidney disease in the United States. [00294] The incidence rates of end-stage renal disease (ESRD) have also increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, followed by the US.

[00295] The mortality rates associated with hemodialysis are striking and indicate that the life expectancy of patients entering into hemodialysis is markedly shortened. At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a 60-year- old patient starting hemodialysis is closer to 4 years (Aurora and Verelli, May 21, 2009. Chronic Renal Failure: Treatment & Medication. Emedicine.

http :// emedicine .medscape. com/ article/238798-treatment) .

Pulmonary fibrosis

[00296] Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases, or by unknown reasons (idiopathic lung fibrosis). The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for the lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy (Lasky JA., Brody AR. (2000), "Interstitial fibrosis and growth factors", Environ Health Perspect.;108 Suppl 4:751-62).

Cardiac fibrosis

[00297] Heart failure is unique among the major cardiovascular disorders in that it alone is increasing in prevalence while there has been a striking decrease in other conditions. Some of this can be attributed to the aging of the populations of the United States and Europe. The ability to salvage patients with myocardial damage is also a major factor, as these patients may develop progression of left ventricular dysfunction due to deleterious remodelling of the heart.

[00298] The normal myocardium is composed of a variety of cells, cardiac myocytes and noncardiomyocytes, which include endothelial and vascular smooth muscle cells and fibroblasts. [00299] Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling of which the net effect is deterioration in cardiac function and the onset of heart failure (Manabe I, et al., (2002), "Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy", Circ Res. 13;91(12): 1103-13).

Burns and scars

[00300] A particular problem which may arise, particularly in fibrotic disease, is contraction of tissues, for example contraction of scars. Contraction of tissues including extracellular matrix components, especially of collagen-including tissues, may occur in connection with many different pathological conditions and with surgical or cosmetic procedures.

Contracture, for example, of scars, may cause physical problems, which may lead to the need for medical treatment, or it may cause problems of a purely cosmetic nature. Collagen is the major component of scar and other contracted tissue and as such is the most important structural component to consider. Nevertheless, scar and other contracted tissue also includes other structural components, especially other extracellular matrix components, for example, elastin, which may also contribute to contraction of the tissue.

[00301] Contraction of collagen-including tissue, which may also include other extracellular matrix components, frequently occurs in the healing of burns. The burns may be chemical, thermal or radiation burns and may be of the eye, the surface of the skin or the skin and the underlying tissues. It may also be the case that there are burns on internal tissues, for example, caused by radiation treatment. Contraction of burnt tissues is often a problem and may lead to physical and/or cosmetic problems, for example, loss of movement and/or disfigurement.

[00302] Skin grafts may be applied for a variety of reasons and may often undergo contraction after application. As with the healing of burnt tissues the contraction may lead to both physical and cosmetic problems. It is a particularly serious problem where many skin grafts are needed as, for example, in a serious burns case.

[00303] Contraction is also a problem in production of artificial skin. To make a true artificial skin it is necessary to have an epidermis made of epithelial cells (keratinocytes) and a dermis made of collagen populated with fibroblasts. It is important to have both types of cells because they signal and stimulate each other using growth factors. The collagen component of the artificial skin often contracts to less than one tenth of its original area when populated by fibroblasts.

[00304] Cicatricial contraction, contraction due to shrinkage of the fibrous tissue of a scar, is common. In some cases the scar may become a vicious cicatrix, a scar in which the contraction causes serious deformity. A patient's stomach may be effectively separated into two separate chambers in an hour-glass contracture by the contraction of scar tissue formed when a stomach ulcer heals. Obstruction of passages and ducts, cicatricial stenosis, may occur due to the contraction of scar tissue. Contraction of blood vessels may be due to primary obstruction or surgical trauma, for example, after surgery or angioplasty. Stenosis of other hollow visci, for examples, ureters, may also occur. Problems may occur where any form of scarring takes place, whether resulting from accidental wounds or from surgery. Conditions of the skin and tendons which involve contraction of collagen-including tissues include post-trauma conditions resulting from surgery or accidents, for example, hand or foot tendon injuries, post-graft conditions and pathological conditions, such as scleroderma, Dupuytren's contracture and epidermolysis bullosa. Scarring and contraction of tissues in the eye may occur in various conditions, for example, the sequelae of retinal detachment or diabetic eye disease (as mentioned above). Contraction of the sockets found in the skull for the eyeballs and associated structures, including extra-ocular muscles and eyelids, may occur if there is trauma or inflammatory damage. The tissues contract within the sockets causing a variety of problems including double vision and an unsightly appearance.

[00305] Other indications include Vocal cord fibrosis, Intestinal fibrosis and Fibrosis associated with brain infarction.

[00306] For further information on different types of fibrosis see: Molina V, et al., (2002), "Fibrotic diseases", Harefuah, 141(11): 973-8, 1009; Yu L, et al, (2002), "Therapeutic strategies to halt renal fibrosis", Curr Opin Pharmacol. 2(2): 177-81; Keane WF and Lyle PA. (2003), "Recent advances in management of type 2 diabetes and nephropathy: lessons from the RENAAL study", Am J Kidney Dis. 41(3 Suppl 2): S22-5; Bohle A, et al, (1989), "The pathogenesis of chronic renal failure", Pathol Res Pract. 185(4):421-40; Kikkawa R, et al., (1997), "Mechanism of the progression of diabetic nephropathy to renal failure", Kidney Int Suppl. 62:S39-40; Bataller R, and Brenner DA. (2001), "Hepatic stellate cells as a target for the treatment of liver fibrosis", Semin Liver Dis. 21(3):437-51; Gross TJ and

Hunninghake GW, (2001) "Idiopathic pulmonary fibrosis", N Engl J Med. 345(7):517-25; Frohlich ED. (2001) "Fibrosis and ischemia: the real risks in hypertensive heart disease", Am J Hypertens;14(6 Pt 2): 194S-199S; Friedman SL. (2003), "Liver fibrosis - from bench to bedside", J Hepatol. 38 Suppl LS38-53; Albanis E, et al, (2003), "Treatment of hepatic fibrosis: almost there", Curr Gastroenterol Rep. 5(l):48-56; (Weber KT. (2000), "Fibrosis and hypertensive heart disease", Curr Opin Cardiol. 15(4):264-72).

Delivery of Nucleic Acid Molecules and Pharmaceutical Formulations

[00307] Nucleic acid molecules may be adapted for use to prevent or treat fibrotic (e.g., liver, kidney, peritoneal, and pulmonary) diseases, traits, conditions and/or disorders, and/or any other trait, disease, disorder or condition that is related to or will respond to the levels of TIMP1 and TIMP2 in a cell or tissue. A nucleic acid molecule may include a delivery vehicle, including liposomes, for administration to a subject, carriers and diluents and their salts, and/or can be present in pharmaceutically acceptable formulations.

[00308] Nucleic acid molecules of the present invention may be delivered to the target tissue by direct application of the naked molecules prepared with a carrier or a diluent.

[00309] The terms "naked nucleic acid" or "naked dsRNA" or "naked siRNA" refers to nucleic acid molecules that are free from any delivery vehicle that acts to assist, promote or facilitate entry into the cell, including viral sequences, viral particles, liposome

formulations, lipofectin or precipitating agents and the like. For example, dsRNA in PBS is "naked dsRNA".

[00310] Nucleic acid molecules disclosed herein may be delivered or administered directly with a carrier or diluent but not any delivery vehicle that acts to assist, promote or facilitate entry to the cell, including viral vectors, viral particles, liposome formulations, lipofectin or precipitating agents and the like.

[00311] Nucleic acid molecules may be delivered or administered to a subject by direct application of the nucleic acid molecules with a carrier or diluent or any other delivery vehicle that acts to assist, promote or facilitate entry into a cell, including viral sequences, viral particular, liposome formulations, lipofectin or precipitating agents and the like.

Polypeptides that facilitate introduction of nucleic acid into a desired subject such as those described in US. Application Publication No. 20070155658 (e.g., a melamine derivative such as 2,4,6-Triguanidino Traizine and 2,4,6-Tramidosarcocyl Melamine, a polyarginine polypeptide, and a polypeptide including alternating glutamine and asparagine residues).

[00312] Methods for the delivery of nucleic acid molecules are described in Akhtar et al., Trends Cell Bio., 2: 139 (1992); Delivery Strategies for Antisense Oligonucleotide

Therapeutics, ed. Akhtar, (1995), Maurer et al, Mol. Membr. Biol, 16: 129-140 (1999); Hofland and Huang, Handb. Exp. Pharmacol, 137: 165-192 (1999); and Lee et al, ACS Symp. Ser., 752: 184-192 (2000); U.S. Pat. Nos. 6,395,713; 6,235,310; 5,225,182;

5,169,383; 5,167,616; 4,959217; 4.925,678; 4,487,603; and 4,486,194 and Sullivan et al, PCT WO 94/02595; PCT WO 00/03683 and PCT WO 02/08754; and U.S. Patent

Application Publication No. 2003077829. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see e.g., Gonzalez et al, Bioconjugate Chem., 10: 1068-1074 (1999); Wang et al, International PCT publication Nos. WO

03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLC A microspheres (see for example U.S. Pat. No. 6,447,796 and U.S. Application Publication No.

2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by

proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722). Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Direct injection of the nucleic acid molecules as disclosed herein, whether subcutaneous, intramuscular, or intradermal, can take place using standard needle and syringe methodologies, or by needle-free technologies such as those described in Corny et al, Clin. Cancer Res., 5: 2330-2337 (1999) and Barry et al,

International PCT Publication No. WO 99/31262. The molecules of as described herein can be used as pharmaceutical agents. Pharmaceutical agents may prevent, modulate the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a subject.

[00313] Nucleic acid molecules may be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through direct dermal application, transdermal application, or injection, with or without their incorporation in biopolymers.

[00314] Delivery systems include surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al, Chem. Pharm. Bull. 1995, 43, 1005-1011).

[00315] Nucleic acid molecules may be formulated or complexed with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine derivatives, including for example polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosami ne (PEI-PEG-triGAL) derivatives, grafted PEIs such as galactose PEI, cholesterol PEI, antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives thereof (see for example Ogris et al., 2001, AAPA PharmSci, 3, 1-11; Furgeson et al, 2003, Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Pharmaceutical Research, 19, 810-817; Choi et al., 2001, Bull. Korean Chem. Soc, 22, 46-52; Bettinger et al, 1999, Bioconjugate Chem., 10, 558-561; Peterson et al, 2002, Bioconjugate Chem., 13, 845-854; Erbacher et al, 1999, Journal of Gene

Medicine Preprint, 1, 1-18; Godbey et al, 1999., PNAS USA, 96, 5177-5181; Godbey et al, 1999, Journal of Controlled Release, 60, 149-160; Diebold et al, 1999, Journal of Biological Chemistry, 274, 19087-19094; Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; Sagara, U.S. Pat. No. 6,586,524 and United States Patent Application Publication No.

20030077829.

[00316] Nucleic acid molecules may be complexed with membrane disruptive agents such as those described in U.S. Patent Application Publication No. 20010007666. The membrane disruptive agent or agents and the nucleic acid molecule may also be complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No.

6,235,310.

[00317] The nucleic acid molecules may be administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues. Solid particulate compositions containing respirable dry particles of micronized nucleic acid compositions can be prepared by grinding dried or lyophilized nucleic acid compositions, and then passing the micronized composition through, for example, a 400 mesh screen to break up or separate out large agglomerates. A solid particulate composition comprising the nucleic acid compositions of contemplated herein can optionally contain a dispersant which serves to facilitate the formation of an aerosol as well as other therapeutic compounds. A suitable dispersant is lactose, which can be blended with the nucleic acid compound in any suitable ratio, such as a 1 to 1 ratio by weight.

[00318] Aerosols of liquid particles may include a nucleic acid molecules disclosed herein and can be produced by any suitable means, such as with a nebulizer (see e.g., U.S. Pat. No. 4,501,729). Nebulizers are commercially available devices which transform solutions or suspensions of an active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers include the active ingredient in a liquid carrier in an amount of up to 40% w/w preferably less than 20% w/w of the formulation. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, e.g., sodium chloride or other suitable salts. Optional additives include preservatives if the formulation is not prepared sterile, e.g., methyl hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants. The aerosols of solid particles including the active composition and surfactant can likewise be produced with any solid particulate aerosol generator. Aerosol generators for administering solid particulate therapeutics to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a therapeutic composition at a rate suitable for human administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which can be delivered by means of an insufflator. In the insufflator, the powder, e.g., a metered dose thereof effective to carry out the treatments described herein, is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically includes from 0.1 to 100 w/w of the formulation. A second type of illustrative aerosol generator includes a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro ethane and mixtures thereof. The formulation can additionally contain one or more co-solvents, for example, ethanol, emulsifiers and other formulation surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavoring agents. Other methods for pulmonary delivery are described in, e.g., US Patent Application No. 20040037780, and U.S. Pat. Nos. 6,592,904; 6,582,728; 6,565,885. PCT Patent Publiction No. WO2008/132723 discloses aerosol delivery of oligonucleotides in general, and of siRNA in particular, to the respiratory system.

[00319] Nucleic acid molecules may be administered to the central nervous system (CNS) or peripheral nervous system (PNS). Experiments have demonstrated the efficient in vivo uptake of nucleic acids by neurons. See e.g., Sommer et al, 1998, Antisense Nuc. Acid Drug Dev., 8, 75; Epa et al, 2000, Antisense Nuc. Acid Drug Dev., 10, 469; Broaddus et al, 1998, J. Neurosurg., 88(4), 734; Karle et al, 1997, Eur. J. PharmocoL, 340(2/3), 153;

Bannai et al, 1998, Brain Research, 784(1,2), 304; Rajakumar et al, 1997, Synapse, 26(3), 199; Wu-pong et al, 1999, BioPharm, 12(1), 32; Bannai et al, 1998, Brain Res. Protoc, 3(1), 83; and Simantov et al, 1996, Neuroscience, 74(1), 39. Nucleic acid molecules are therefore amenable to delivery to and uptake by cells in the CNS and/or PNS.

[00320] Delivery of nucleic acid molecules to the CNS is provided by a variety of different strategies. Traditional approaches to CNS delivery that can be used include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening of the blood-brain barrier. Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. Furthermore, gene therapy approaches, e.g., as described in Kaplitt et al, U.S. Pat. No. 6,180,613 and Davidson, WO 04/013280, can be used to express nucleic acid molecules in the CNS.

[00321] Delivery systems may include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone). In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer. Examples of liposomes which can be used include the following: (1) CellFectin, 1 : 1.5 (M/M) liposome formulation of the cationic lipid Ν,ΝΙ,ΝΙΙ,ΝΙΙΙ-tetramethyl- N,NI,NII,NIII-tetrapalmit-y-spermine and dioleoyl phosphatidylethanolamine (DOPE) (GIBCO BRL); (2) Cytofectin GSV, 2: 1 (M/M) liposome formulation of a cationic lipid and DOPE (Glen Research); (3) DOTAP (N-[l-(2,3-dioleoyloxy)-N,N,N-tri-methyl- ammoniummethylsulfate) (Boehringer Manheim); and (4) Lipofectamine, 3: 1 (M/M) liposome formulation of the polycationic lipid DOSPA, the neutral lipid DOPE (GIBCO BRL) and Di- Alkylated Amino Acid (DiLA2).

[00322] Delivery systems may include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid). [00323] Nucleic acid molecules may be formulated or complexed with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine derivatives, including for example grafted PEIs such as galactose PEI, cholesterol PEI, antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives thereof (see for example Ogris et al., 2001, AAPA PharmSci, 3, 1-11; Furgeson et al, 2003, Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Pharmaceutical Research, 19, 810-817; Choi et al., 2001, Bull. Korean Chem. Soc, 22, 46-52; Bettinger et al, 1999, Bioconjugate Chem., 10, 558-561; Peterson et al, 2002, Bioconjugate Chem., 13, 845-854; Erbacher et al, 1999, Journal of Gene Medicine Preprint, 1, 1-18; Godbey et al, 1999., PNAS USA, 96, 5177-5181; Godbey et al, 1999, Journal of Controlled Release, 60, 149-160; Diebold et al, 1999, Journal of Biological Chemistry, 274, 19087-19094; Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; and Sagara, U.S. Pat. No. 6,586,524.

[00324] Nucleic acid molecules may include a bioconjugate, for example a nucleic acid conjugate as described in Vargeese et al, U.S. Ser. No. 10/427,160; U.S. Pat. No.

6,528,631; U.S. Pat. No. 6,335,434; U.S. Pat. No. 6,235,886; U.S. Pat. No. 6,153,737; U.S. Pat. No. 5,214,136; U.S. Pat. No. 5,138,045.

[00325] Compositions, methods and kits disclosed herein may include an expression vector that includes a nucleic acid sequence encoding at least one nucleic acid molecule as provided herein in a manner that allows expression of the nucleic acid molecule. Methods of introducing nucleic acid molecules or one or more vectors capable of expressing the strands of dsRNA into the environment of the cell will depend on the type of cell and the make up of its environment. The nucleic acid molecule or the vector construct may be directly introduced into the cell (i.e., intracellularly); or introduced extracellularly into a cavity, interstitial space, into the circulation of an organism, introduced orally, or may be introduced by bathing an organism or a cell in a solution containing dsRNA. The cell is preferably a mammalian cell; more preferably a human cell. The nucleic acid molecule of the expression vector can include a sense region and an antisense region. The antisense region can include a sequence complementary to a RNA or DNA sequence encoding TIMP1 and TIMP2 and the sense region can include a sequence complementary to the antisense region. The nucleic acid molecule can include two distinct strands having complementary sense and antisense regions. The nucleic acid molecule can include a single strand having complementary sense and antisense regions.

[00326] Nucleic acid molecules that interact with target RNA molecules and down-regulate gene encoding target RNA molecules (e.g., target RNA molecules referred to by Genbank Accession numbers herein) may be expressed from transcription units inserted into DNA or RNA vectors. Recombinant vectors can be DNA plasmids or viral vectors. Nucleic acid molecule expressing viral vectors can be constructed based on, but not limited to, adeno- associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the nucleic acid molecules can be delivered as described herein, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecules bind and down-regulate gene function or expression via RNA interference (RNAi). Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex -planted from a subject followed by reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell.

[00327] Expression vectors may include a nucleic acid sequence encoding at least one nucleic acid molecule disclosed herein, in a manner which allows expression of the nucleic acid molecule. For example, the vector may contain sequence(s) encoding both strands of a nucleic acid molecule that include a duplex. The vector can also contain sequence(s) encoding a single nucleic acid molecule that is self-complementary and thus forms a nucleic acid molecule. Non-limiting examples of such expression vectors are described in Paul et al, 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al, 2002, Nature Biotechnology, 19, 500; and Novina et al, 2002, Nature Medicine, advance online publication doi: 10.1038/nm725. Expression vectors may also be included in a mammalian (e.g., human) cell.

[00328] An expression vector may include a nucleic acid sequence encoding two or more nucleic acid molecules, which can be the same or different. Expression vectors may include a sequence for a nucleic acid molecule complementary to a nucleic acid molecule referred to by a Genbank Accession number NM_003254 (TIMP1) or NM_003255 (TIMP2).

I l l [00329] An expression vector may encode one or both strands of a nucleic acid duplex, or a single self-complementary strand that self hybridizes into a nucleic acid duplex. The nucleic acid sequences encoding nucleic acid molecules can be operably linked in a manner that allows expression of the nucleic acid molecule (see for example Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al, 2002, Nature Biotechnology, 19, 500; and Novina et al, 2002, Nature Medicine, advance online publication doi: 10.1038/nm725).

[00330] An expression vector may include one or more of the following: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) an intron and d) a nucleic acid sequence encoding at least one of the nucleic acid molecules, wherein said sequence is operably linked to the initiation region and the termination region in a manner that allows expression and/or delivery of the nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5 ' side or the 3 '-side of the sequence encoding the nucleic acid molecule; and/or an intron

(intervening sequences).

[00331] Transcription of the nucleic acid molecule sequences can be driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. USA, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al, 1993, Methods EnzymoL, 217, 47-66; Zhou et al, 1990, Mol. Cell. Biol, 10, 4529-37). Several investigators have demonstrated that nucleic acid molecules expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al, 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Yu et al, 1993, Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al, 1992, EMBO J., 11, 4411-8; Lisziewicz et al, 1993, Proc. Natl. Acad. Sci. U.S.A, 90, 8000-4; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as siNA in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra;

Noonberg et al, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al, U.S. Pat. No.

5,624,803; Good et al, 1997, Gene Ther., 4, 45; Beigelman et al, International PCT

Publication No. WO 96/18736. The above nucleic acid transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno- associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (see Couture and Stinchcomb, 1996 supra).

[00332] Nucleic acid molecule may be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al, 1991, Proc. Natl. Acad. Sci. USA, 88, 10591- 5; Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al, 1992, J. Virol, 66, 1432-41; Weerasinghe et al, 1991, J. Virol, 65, 5531-4; Ojwang et al, 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al, 1990 Science, 247, 1222-1225; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Good et al, 1997, Gene Therapy, 4, 45. Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al, 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al, 1994, J. Biol. Chem., 269, 25856.

[00333] A viral construct packaged into a viral particle would accomplish both efficient introduction of an expression construct into the cell and transcription of dsRNA construct encoded by the expression construct.

[00334] Methods for oral introduction include direct mixing of RNA with food of the organism, as well as engineered approaches in which a species that is used as food is engineered to express an RNA, then fed to the organism to be affected. Physical methods may be employed to introduce a nucleic acid molecule solution into the cell. Physical methods of introducing nucleic acids include injection of a solution containing the nucleic acid molecule, bombardment by particles covered by the nucleic acid molecule, soaking the cell or organism in a solution of the R A, or electroporation of cell membranes in the presence of the nucleic acid molecule.

[00335] Other methods known in the art for introducing nucleic acids to cells may be used, such as lipid-mediated carrier transport, chemical mediated transport, such as calcium phosphate, and the like. Thus the nucleic acid molecules may be introduced along with components that perform one or more of the following activities: enhance RNA uptake by the cell, promote annealing of the duplex strands, stabilize the annealed strands, or otherwise increase inhibition of the target gene.

[00336] The nucleic acid molecules or the vector construct can be introduced into the cell using suitable formulations. One formulation comprises a lipid formulation such as in Lipofectamine™ 2000 (Invitrogen, CA, USA. Lipid formulations can also be administered to animals such as by intravenous, intramuscular, or intraperitoneal injection, or orally or by inhalation or other methods as are known in the art. When the formulation is suitable for administration into animals such as mammals and more specifically humans, the formulation is also pharmaceutically acceptable. Pharmaceutically acceptable formulations for administering oligonucleotides are known and can be used. In some instances, it may be preferable to formulate dsRNA in a buffer or saline solution and directly inject the formulated dsRNA into cells, as in studies with oocytes. The direct injection of dsRNA duplexes may also be done. For suitable methods of introducing dsRNA see U.S. published patent application No. 2004/0203145, 20070265220 which are incorporated herein by reference.

[00337] Polymeric nanocapsules or microcapsules facilitate transport and release of the encapsulated or bound dsRNA into the cell. They include polymeric and monomeric materials, especially including polybutylcyanoacrylate. A summary of materials and fabrication methods has been published (see Kreuter, 1991). The polymeric materials which are formed from monomeric and/or oligomeric precursors in the

polymerization/nanoparticle generation step, are per se known from the prior art, as are the molecular weights and molecular weight distribution of the polymeric material which a person skilled in the field of manufacturing nanoparticles may suitably select in accordance with the usual skill.

[00338] Nucleic acid moles may be formulated as a microemulsion. A microemulsion is a system of water, oil and amphiphile which is a single optically isotropic and

thermodynamically stable liquid solution. Typically microemulsions are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a 4th component, generally an intermediate chain-length alcohol to form a transparent system.

[00339] Surfactants that may be used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DA0750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules.

Water Soluble Crosslinked Polymers

[00340] Delivery formulations can include water soluble degradable crosslinked polymers that include one or more degradable crosslinking lipid moiety, one or more PEI moiety, and/or one or more mPEG (methyl ether derivative of PEG (methoxypoly (ethylene glycol)).

[00341] Degradable lipid moieties preferably include compounds having the following structural motif:

(A) [00342] In the above formula, ester linkages are biodegradable groups, R represents a relatively hydrophobic "lipo" group, and the structural motif shown occurs m times where m is in the range of about 1 to about 30. For example, in certain embodiments R is selected from the group consisting of C2-C50 alkyl, C2-C50 heteroalkyl, C2 - Cso alkenyl, C2 - Cso heteroalkenyl, Cs-Cso aryl; C2-C50 heteroaryl; C2-C50 alkynyl, C2-C50 heteroalkynyl, C2 - Cso carboxyalkenyl, and C2 - Cso carboxyheteroalkenyl. In preferred embodiments, R is a saturated or unsaturated alkyl having 4 to 30 carbons, more preferably 8 to 24 carbons or a sterol, preferably a cholesteryl moiety. In preferred embodiments, R is oleic, lauric, myristic, palmitic margaric, stearic, arachidic, behenic, or lignoceric. In a most preferred embodiment, R is oleic.

[00343] The N in formula (B) may have an electron pair or a bond to a hydrogen atom. When N has an electron pair, the recurring unit may be cationic at low pH.

[00344] The degradable crosslinking lipid moiety may be reacted with a polyethyleneimine (PEI) as shown in Scheme A below:

Sche

PEI

[00345] In formula (A), R has the same meanings as described above. The PEI may contain recurring units of formula (B) in which x is an integer in the range of about 1 to about 100 and is an integer in the range of about 1 to about 100.

[00346] The reaction illustrated in Scheme A may be carried out by intermixing the PEI and the diacrylate (I) in a mutual solvent such as ethanol, methanol or dichloromethane with stirring, preferably at room temperature for several hours, then evaporating the solvent to recover the resulting polymer. While not wishing to be bound to any particular theory, it is believed that the reaction between the PEI and diacrylate (I) involves a Michael reaction between one or more amines of the PEI with double bond(s) of the diacrylate (see J. March, Advanced Organic Chemistry 3rd Ed., pp. 711-712 (1985)). The diacrylate shown in Scheme A may be prepared in the manner as described in US Application No. 11/216,986 (US Publication No. 2006/0258751).

[00347] The molecular weight of the PEI is preferably in the range of about 200 to 25,000 Daltons more preferably 400 to 5,000 Daltons, yet more preferably 600 to 2000 Daltons. PEI may be either branched or linear.

[00348] The molar ratio of PEI to diacrylate is preferably in the range of about 1 :2 to about 1 :20. The weight average molecular weight of the cationic lipopolymer may be in the range of about 500 Daltons to about 1,000,000 Daltons preferably in the range of about 2,000 Daltons to about 200,000 Daltons. Molecular weights may be determined by size exclusion chromatography using PEG standards or by agarose gel electrophoresis.

[00349] The cationic lipopolymer is preferably degradable, more preferably biodegradable, e.g., degradable by a mechanism selected from the group consisting of hydrolysis, enzyme cleavage, reduction, photo-cleavage, and sonication. While not wishing to be bound to any particular theory, but it is believed that degradation of the cationic lipopolymer of formula (II) within the cell proceeds by enzymatic cleavage and/or hydrolysis of the ester linkages. [00350] Synthesis may be carried out by reacting the degradable lipid moiety with the PEI moiety as described above. Then the mPEG (methyl ether derivative of PEG (methoxypoly (ethylene glycol)), is added to form the degradable crosslinked polymer. In preferred embodiments, the reaction is carried out at room temperature. The reaction products may be isolated by any means known in the art including chromatographic techniques. In a preferred embodiment, the reaction product may be removed by precipitation followed by centrifugation.

Dosages

[00351] The useful dosage to be administered and the particular mode of administration will vary depending upon such factors as the cell type, or for in vivo use, the age, weight and the particular animal and region thereof to be treated, the particular nucleic acid and delivery method used, the therapeutic or diagnostic use contemplated, and the form of the formulation, for example, suspension, emulsion, micelle or liposome, as will be readily apparent to those skilled in the art. Typically, dosage is administered at lower levels and increased until the desired effect is achieved.

[00352] When lipids are used to deliver the nucleic acid, the amount of lipid compound that is administered can vary and generally depends upon the amount of nucleic acid being administered. For example, the weight ratio of lipid compound to nucleic acid is preferably from about 1 : 1 to about 30: 1, with a weight ratio of about 5:1 to about 10: 1 being more preferred.

[00353] A suitable dosage unit of nucleic acid molecules may be in the range of 0.001 to 0.25 milligrams per kilogram body weight of the recipient per day, or in the range of 0.01 to 20 micrograms per kilogram body weight per day, or in the range of 0.01 to 10 micrograms per kilogram body weight per day, or in the range of 0.10 to 5 micrograms per kilogram body weight per day, or in the range of 0.1 to 2.5 micrograms per kilogram body weight per day.

[00354] Suitable amounts of nucleic acid molecules may be introduced and these amounts can be empirically determined using standard methods. Effective concentrations of individual nucleic acid molecule species in the environment of a cell may be about 1 femtomolar, about 50 femtomolar, 100 femtomolar, 1 picomolar, 1.5 picomolar, 2.5 picomolar, 5 picomolar, 10 picomolar, 25 picomolar, 50 picomolar, 100 picomolar, 500 picomolar, 1 nanomolar, 2.5 nanomolar, 5 nanomolar, 10 nanomolar, 25 nanomolar, 50 nanomolar, 100 nanomolar, 500 nanomolar, 1 micromolar, 2.5 micromolar, 5 micromolar, 10 micromolar, 100 micromolar or more.

[00355] Dosage may be from 0.01 μg to 1 g per kg of body weight (e.g., 0.1 μg, 0.25 μg, 0.5 μg, 0.75 μg, 1 μg, 2.5 μg, 5 μg, 10 μg, 25 μg, 50 μg, 100 μg, 250 μg, 500 μg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg per kg).

[00356] Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per subject per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.

[00357] It is understood that the specific dose level for any particular subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[00358] Pharmaceutical compositions that include the nucleic acid molecule disclosed herein may be administered once daily, qid, tid, bid, QD, or at any interval and for any duration that is medically appropriate. However, the therapeutic agent may also be dosed in dosage units containing two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In that case, the nucleic acid molecules contained in each sub-dose may be correspondingly smaller in order to achieve the total daily dosage unit. The dosage unit can also be compounded for a single dose over several days, e.g., using a conventional sustained release formulation which provides sustained and consistent release of the dsR A over a several day period. Sustained release formulations are well known in the art. The dosage unit may contain a corresponding multiple of the daily dose. The composition can be compounded in such a way that the sum of the multiple units of a nucleic acid together contain a sufficient dose. Pharmaceutical compositions, kits, and containers

[00359] Also provided are compositions, kits, containers and formulations that include a nucleic acid molecule (e.g., an siNA molecule) as provided herein for reducing expression of TIMPl and TIMP2 for administering or distributing the nucleic acid molecule to a patient. A kit may include at least one container and at least one label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass, metal or plastic. The container can hold amino acid sequence(s), small molecule(s), nucleic acid sequence(s), cell population(s) and/or antibody(s). In one embodiment, the container holds a polynucleotide for use in examining the mRNA expression profile of a cell, together with reagents used for this purpose. In another embodiment a container includes an antibody, binding fragment thereof or specific binding protein for use in evaluating TIMPl and TIMP2 protein expression cells and tissues, or for relevant laboratory, prognostic, diagnostic, prophylactic and therapeutic purposes; indications and/or directions for such uses can be included on or with such container, as can reagents and other compositions or tools used for these purposes. Kits may further include associated indications and/or directions; reagents and other compositions or tools used for such purpose can also be included.

[00360] The container can alternatively hold a composition that is effective for treating, diagnosis, prognosing or prophylaxing a condition and can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agents in the composition can be a nucleic acid molecule capable of specifically binding TIMPl and TIMP2 and/or modulating the function of TIMPl and TIMP2.

[00361] A kit may further include a second container that includes a pharmaceutically- acceptable buffer, such as phosphate -buffered saline, Ringer's solution and/or dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, stirrers, needles, syringes, and/or package inserts with indications and/or instructions for use.

[00362] The units dosage ampoules or multidose containers, in which the nucleic acid molecules are packaged prior to use, may include an hermetically sealed container enclosing an amount of polynucleotide or solution containing a polynucleotide suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The

polynucleotide is packaged as a sterile formulation, and the hermetically sealed container is designed to preserve sterility of the formulation until use.

[00363] The container in which the polynucleotide including a sequence encoding a cellular immune response element or fragment thereof may include a package that is labeled, and the label may bear a notice in the form prescribed by a governmental agency, for example the Food and Drug Administration, which notice is reflective of approval by the agency under Federal law, of the manufacture, use, or sale of the polynucleotide material therein for human administration.

[00364] Federal law requires that the use of pharmaceutical compositions in the therapy of humans be approved by an agency of the Federal government. In the United States, enforcement is the responsibility of the Food and Drug Administration, which issues appropriate regulations for securing such approval, detailed in 21 U.S.C. § 301-392.

Regulation for biologic material, including products made from the tissues of animals is provided under 42 U.S.C. § 262. Similar approval is required by most foreign countries. Regulations vary from country to country, but individual procedures are well known to those in the art and the compositions and methods provided herein preferably comply accordingly.

[00365] The dosage to be administered depends to a large extent on the condition and size of the subject being treated as well as the frequency of treatment and the route of

administration. Regimens for continuing therapy, including dose and frequency may be guided by the initial response and clinical judgment. The parenteral route of injection into the interstitial space of tissues is preferred, although other parenteral routes, such as inhalation of an aerosol formulation, may be required in specific administration, as for example to the mucous membranes of the nose, throat, bronchial tissues or lungs.

[00366] As such, provided herein is a pharmaceutical product which may include a polynucleotide including a sequence encoding a cellular immune response element or fragment thereof in solution in a pharmaceutically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to express a cellular immune response element or fragment thereof, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human administration.

Indications

[00367] The nucleic acid molecules disclosed herein can be used to treat diseases, conditions or disorders associated with TIMPl and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis and any other disease or conditions that are related to or will respond to the levels of TIMPl and TIMP2 in a cell or tissue. As such, compositions, kits and methods disclosed herein may include packaging a nucleic acid molecule disclosed herein that includes a label or package insert. The label may include indications for use of the nucleic acid molecules such as use for treatment or prevention of liver fibrosis, peritoneal fibrosis, kidney fibrosis and pulmonary fibrosis, and any other disease or conditions that are related to or will respond to the levels of TIMPl and TIMP2 in a cell or tissue. A label may include an indication for use in reducing expression of TIMPl and TIMP2. A "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products to be combined with the packaged product, and/or warnings concerning the use of such therapeutic products, etc.

[00368] Those skilled in the art will recognize that two or more siTIMPl and or siTIMP2 may be combined or that other anti-fibrosis treatments, drugs and therapies known in the art can be readily combined with the nucleic acid molecules herein (e.g. siNA molecules) and are hence contemplated herein.

[00369] The methods and compositions provided herein will now be described in greater detail by reference to the following non-limiting examples. EXAMPLES

Example 1

siRNA sequences

[00370] siRNA sequences for TIMP-1, TIMP-2, positive control and negative control are listed in Tabls C and D. ΙΟΟμΜ siRNA stock solution was prepared by dissolving in nucrease free water (Ambion). In the "Sequence" columns in Tables C and D, lower case letters represent unmodified ribonucleotides, "T" represents deoxyribothymidine.

Table C

Table D

AS (3 * ->5 * ) TTauagaguaacguccuuucc 20

Example 2

siRNA delivery

[00371] HT-1080 cell (Japanese Collection of Research Bioresources) was maintained incubated in DMEM (Sigma, Cat# D6546) with 10% fetal bovine serum (FBS; Hyclone, Cat.# SH30070.03) and 1% volume/volume L-Glutamine-penicillin-streptomycin solution (Sigma, Cat.# Gl 146) and 1% volume/volume L-Glutamine solution (Sigma, Cat.# G7513). Before delivering siRNA, cells were seeded in 6-well plate (Nunc. #140675) at the density of 5x10 3 cells per well and incubated at 37°C with 7.5% C0 2 for 2 days. siRNAs for TIMPl were transfected to the cells with VA-coupled liposome (V A- liposome) as described by Sato et al. (Sato Y. et al. Nature Biotechnology 2008. Vol.26, p431) and siRNAs for TIMP2 were delivered with VA-conjugated cationic polymer (VA-polymer), synthesized in- house at the ratio of 5: 1 (VA-polymer:siRNA, weight per weight). The final concentration of siRNA was 50nM. 2-hours after siRNA delivery, cell culture medium was replaced to fresh DMEM with 10% FBS and incubated for 2 overnight at 37°C with 7.5% C0 2 .

Example 3

[00372] Gene knocking down assessment of siRNA by RT-PCR

[00373] After transfection as described in Example 2, total RNA was isolated with

QIAshreader QIAGEN, 79654) and RNeasy Mini Kit (QIAGEN, 74104) by following manufacturer's protocol. 1 μg of the isolated total RNA was used for cDNA preparation with Hicapacity RNA-to-cDNA Master Mix (Applied Biosystems, 4390779) as indicated by manufacturer's protocol. Then, 0.05 μg of cDNA was employed for polymerase chain reaction (PCR) with ExTaq (TaKaRa, RR001B) polymerase by following supplied manual. PCR primers for detection of each gene are listed in excel file. PCR condition was as follows: 94°C 4min, then 4 °C 30sec, 63 °C 30sec, 72 °C lmin for 23 cycles, 72 °C 5min before termination. 15μ1 of PCR products for TIMP-1 or TIMP-2 gene and 5μ1 for GAPDH gene were identified by agarose gel electrophoresis.

[00374] Figure 2 indicates knock down efficacy of siRNAs for TIMP1 as measured by qPCR. The amount of PCR product from cells transfected with TIMP-1 siRNA, e.g.

TIMP1-A (SEQ ID NOS:5 and 6), TIMP1-B (SEQ ID NOS:7 and 8) or TIMPl-C (SEQ ID NOS:9 and 10), was less than that from untreated cells, therefore, those siRNA for TIMP1 gene are capable to knock down the target gene.

[00375] Figure 3 represents knock down efficacy of siRNAs for TIMP2 as measured by qPCR: TIMP2-A (SEQ ID NOS: l 1 and 12), TIMP2-B (SEQ ID NOS: 13 and 14), TIMP2-C (SEQ ID NOS: 15 and 16), TIMP2-D (SEQ ID NOS: 17 and 18) and TIMP2-E (SEQ ID NOS: 19 and 20). TIMP2 siRNA showed target gene knock down and level of gene silencing was dependent on the sequence.

Example 4

[00376] Treatment of liver cirrhosis in rats with siTIMPl and siTIMP2

[00377] Liver cirrhosis animal model: Liver cirrhosis was induced in rats using the method described by Sato et al., (Sato Y. et al. Nat Biotech 2008. 26:431). Briefly, liver cirrhosis was induced in 4 week-old male SD rats by injecting them dimethylnitrosoamine (DMN) (Wako Chemicals, Japan) as follows: 0.5% DMN in phosphate-buffered saline (PBS) was administered to rats intraperitoneally at a dose of 2 ml/kg per body weight for 3 consecutive days per week. Specifically, DMN solution was injected on days 0 (start of the experiment),

2, 4, 7, 9, 11, 14, 16, 18, 21, 23, 25, 28, 30, 32, 34 and 36.

[00378] siRNA sequence for TIMP1 ("siTIMPl-A")

S (5 * ->3 * ) ccaccuuauaccagcguuaTT (SEQ ID NO:5)

AS (3'->5') TTgguggaauauggucgcaau (SEQ ID NO:6)

[00379] siRNA sequence for TIMP2 ("siTIMP2-C")

S (5 * ->3 * ) gcagauaaagauguucaaaTT (SEQ ID NO: 15)

AS (3'->5') TTcgucuauuucuacaaguuu (SEQ ID NO: 16) [00380] Α10μ§/μ1 siRNA stock solution was prepared by dissolving siRNA duplexes (siTIMPl or siTIMP2) in nuclease free water (Ambion). For treatment of rats, siRNA was formulated with vitamin A-coupled liposome as described by Sato et al (Sato Y. et al.

Nature Biotech 2008. Vol.26, p431). The vitamin A (VA)-liposome-siRNA formulation consisted of 0.33 μιηοΐ/ιηΐ of VA, 0.33 μιηοΐ/ιηΐ of liposome (Coatsome EL-01-D, NOF Corporation) and 0.5 μg/μl of siRNA in 5% glucose solution.

[00381] Injection solution for siRNA delivered at a concentration of 0.75 mg/Kg

[00382] The liposomes were prepared at a concentration of ImM by addition of nuclease- free water, and left for 15 min at room temperature before use. To prepare VA-coupled liposomes, 100 nmol of vitamin A (dissolved in DMSO) was mixed with the liposomes (100 nmol) by vortex for 15 seconds at R.T.

[00383] The siRNA duplexes (150μg) were prepared at a concentration of 10μg/μl by addition of nuclease-free water. A 5% glucose (175μ1) solution was added to the liposomal suspension. (Total volume of 300μ1). The VA- liposome- siRNA solutions were injected to each rat to a final concentration of 0.75 ml/Kg body weight.

[00384] Injection solution for siRNA delivered at a concentration of 1.5 mg/Kg

[00385] The liposomes were prepared at a concentration of ImM by addition of nuclease- free water, and left to stand for 15 min before use. To prepare VA-coupled liposome, 200 nmol of vitamin A (dissolved in DMSO) was mixed with the liposome (200 nmol) by vortex for 15 seconds at R.T.

[00386] The siRNA duplexes (300μg) were prepared at a concentration of 10μg/μl by addition of nuclease-free water. A 5% glucose (50μ1) solution was added to the liposomal suspension. (Total volume 300μ1). The VA- liposome- siRNA solutions were injected to each rat to a final concentration of 1.5 ml/Kg body weight.

[00387] siRNA treatment

[00388] The siRNA treatment was carried out from day 28 for 5 times by intravenous injection. In detail, rats were treated with siRNA on days 28, 30, 32, 34 and 36 post DMN treatment. Rats were sacrificed on day 38 or 39. Two different siRNA species (siTIMPl-A and siTIMP2-C) and 2 different doses (0.75mg siRNA per kg body weight, 1.5 mg siRNA per kg body weight) were tested. Details of tested groups and number of animals in each group are as follows:

1) Control animals: Liver cirrhosis was induced by DMN injection, and a 5% glucose was administered (n=9)

2) VA-Lip-siTIMPl-A 0.75 mg/Kg (n=9)

3) VA-Lip-siTIMPl-A 1.5 mg/Kg (n=9)

4) VA-Lip-siTIMP2-C 0.75 mg/Kg (n=9)

5) VA-Lip-siTIMP2-C 1.5 mg/Kg (n=9)

6) Sham (PBS was injected instead of DMN. 5% Glucose was administered instead of siRNA) (n=5)

7) Untreated control animals (Intact) (n=5) [00389] Evaluation of therapeutic efficacy

[00390] On day 38, 2 out of 10 animals in "siTIMP2-C" group died and were not analyzed further. However, other animals were survived before the sacrifice. After rats were sacrificed, liver tissues were fixed in 10% formalin. The left lobe of the liver was embedded in paraffin for tissue slide preparation. Tissue slides were stained with Sirius red as well as hematoxylin and eosin (HE). Sirius red staining was employed to visualize collagen- deposited area and determine the level of cirrhosis. HE staining was used for nuclei and cytoplasm as counter-staining. Each slide was observed under microscope (BZ-9000, Keyence Corp. Japan) and the percentage of Sirius red-stained area per slide was determined by image analysis software attached to the microscope. At least 4 slides per each liver were prepared for image analysis, and whole area of each slide (slice of liver) was captured by camera and analyzed. Statistic analysis was carried out by t-test analysis. Results are shown in Figure 4. Liver sections were photographed at x32 magnification. The fibrotic areas were calculated as the mean of 4 liver sections. The bar graph summarizes the digital quantification of staining for each group. Statistical values are as follows: * = P<0.05, ** = P < 0.01, *** = P<0.001

[00391] Figure 4 represents the fibrotic area in liver sections. The area of fibrosis in the "diseased rat" (group 1) was higher than "sham" (group 6) or "untreated" (group 7) groups. Therefore, DMN treatment induced collagen deposition in liver, typical of liver fibrosis. The area of fibrosis was significantly reduced by the treatment of siRNA targeting TIMPl gene (groups 2 and 3), compared with "diseased rat" group, indicating that siRNA to TIMPl has therapeutic efficacy in treating fibrotic diseases and disorders.

Example 5

[00392] Selecting TIMPl and TIMP2 Nucleic Acid Molecule Sequences:

[00393] Nucleic acid molecules (e.g., siNA < 25 nucleotides) against TIMPl and TIMP2 were designed using a proprietary database. Candidate sequences are validated by in vitro knock down assays. Details of the nucleic acids set forth in the Tables are

[00394] The Tables (Al, A2, A5, A6, Bl, B2, B5, B6) include

a. 19-mer and 18-mer siRNAs (sense and corresponding antisense sequences to form duplex siRNA) predicted to be active by a proprietary database and excludes known 19-mer siRNAs;

b. siRNAs which target human and at least two additional species (cross species) selected from dog, rat, mouse and rabbit and are predicted to be active;

i. inclusion of cross-species siRNA compounds are siRNA with full match to the indicated target ("Sense") and

ii. inclusion of siRNAs with mismatches relative to the target, at

positions 1, 19 (5'>3') or both.

[00395] The Tables of "preferred" siRNA (A3, A7, B3, B7) include sense and

corresponding antisense sequences that were selected as follows:

i. Selection for cross species to human (H) and rat (Rt) and inclusion of sequences with 1 MM (single mismatch (MM)) to rat target in positions other than 1/19 (5'>3')

ii. Addition of predicted active siRNA compounds that don't target rat but target at least two other species selected from dog, mouse and rabbit. 111 Addition of best siRNA targeting human or human + rhesus

IV, Exclusion of siRNAs that target miRNA seed sequence

V, Exclusion of siRNAs with high G/C content

VI Exclusion of siRNAs targeting multiple SNPs

[00396] The Tables labeled as "lowest predicted OT effect" (Tables A4, A8, B4 and B8) relate to siRNA from the "preferred" Tables having best off-target (OT) features including c. Column labeled "Crosses" - Indicates species specificity as follows: i. H/Rt = siRNA targeting at least human and rat

ii. H/Rt (Rt cross - with 1MM) = siRNA targeting at least human and rat.

Target match to rat is partial and there is one mismatch at a position other than 1 or 19

iii. Other (w/o Rt) - siRNA targets human and other species but not rat iv. H +/- Rh = siRNA targeting only human or human and Rhesus but no other species

[00397] Column labeled "# in HTS list" - Indicates the siRNA number in the preceding "Preferred" Table (A3, A7, B3, B7).

2. Selection is done in the following manner:

i. Mismatches (MM) are identified in positions 2-18 of the guide strand.

MM in positions 1 and 19 are NOT considered as mismatches.

ii. Exclusion of siRNAs having complete match (0 MM) to other genes iii. Exclusion of siRNAs having 1 MM in position 17 or 18 (of AS strand) to other genes

iv. Preference (ranking of predicted OT activity):

1 - has 3MM within positions 2-16 of AS (5'>3').

2 - has 2MM to 1-4 gene targets within positions 2-16

3 - has 2MM to 5-9 gene targets within (positions 2-16)

4 - targets 10-20 genes with 2MM (positions 2-16)

[00398] Sequences of sense and antisense oligonucleotides useful in the preparation of siRNA molecules are disclosed in Tables Al, A2, A3, A4, A5, A6, A7, A8, Bl, B2, B3, B4, B5, B6, B7, B8 (Tables A1-B8) infra. Best OT refers to least number of matches to off- target genes. [00399] The following abbreviations are used in the Tables A1-B8 (Tables Al, A2, A3, A4, A5, A6, A7 A8, Bl, B2, B3, B4, B5, B6, B7 and B8) herein: "other spec or Sp." refers to cross species identity with other animals: D or Dg-dog, Rt-rat, Rb-rabbit, Rh-rhesus monkey, Pg- Pig, M or Ms-Mouse, Ck-Chicken, Cw-Cow; ORF: open reading frame. 19- mers, and 18+1-mers refer to oligomers of 19 and 18+1 (U at position 1 of Antisense, A at position 19 of sense strand or A at position 1 of Antisense, U at position 19 of sense strand) ribonucleic acids in length, respectively.

Table Al 19-mer siTIMPl

GGCAGUCCCUGCGGUCCCA 56 UGGGACCGCAGGGACUGCC 164 [787-805] ORF

GAUGUAUAAAGGGUUCCAA 57 UUGGAACCCUUUAUACAUC 165 R [392-410] ORF

CUGGCAUCCUGUUGUUGCU 58 AGCAACAACAGGAUGCCAG 166 [217-235] ORF

GGACGGACCAGCUCCUCCA 59 UGGAGGAGCUGGUCCGUCC 167 R [700-718] ORF

GAGUGGCACUCAUUGCUUG 60 CAAGCAAUGAGUGCCACUC 168 Rh [680-698] ORF

AGAGUGUCUGCGGAUACUU 61 AAGUAUCCGCAGACACUCU 169 Rh [460-478] ORF

ACCAGACCACCUUAUACCA 62 UGGUAUAAGGUGGUCUGGU 170 Rh [349-367] ORF

CACCAAGACCUACACUGUU 63 AACAGUGUAGGUCUUGGUG 171 Rh [608-626] ORF

GGCAUCCUGUUGUUGCUGU 64 ACAGCAACAACAGGAUGCC 172 Rh [219-237] ORF

CCUGAAUCCUGCCCGGAGU 65 ACUCCGGGCAGGAUUCAGG 173 [811-829] ORF+3'UTR

GUCAACCAGACCACCUUAU 66 AUAAGGUGGUCUGGUUGAC 174 Rh [345-363] ORF

GGACACCAGAAGUCAACCA 67 UGGUUGACUUCUGGUGUCC 175 Rh [334-352] ORF

AGCGUUAUGAGAUCAAGAU 68 AUCUUGAUCUCAUAACGCU 176 Rh,Dg,Rt [367-385] ORF

UGCACAGUGUUUCCCUGUU 69 AACAGGGAAACACUGUGCA 177 Rh,Rt,M [639-657] ORF

ACUGCAGAGUGGCACUCAU 70 AUGAGUGCCACUCUGCAGU 178 Rh [674-692] ORF

CCCAUCUUUCUUCCGGACA 71 UGUCCGGAAGAAAGAUGGG 179 [869-887] 3'UTR

GUGAGGAAUGCACAGUGUU 72 AACACUGUGCAUUCCUCAC 180 Rh [631-649] ORF

CCUCCAAGGCUCUGAAAAG 73 CUUUUCAGAGCCUUGGAGG 181 Rh [713-731] ORF

CAUCACUACCUGCAGUUUU 74 AAAACUGCAGGUAGUGAUG 182 [545-563] ORF

AGCUGAAGCCUGCACAGUG 75 CACUGUGCAGGCUUCAGCU 183 [833-851] 3'UTR

GCACAGUGUCCACCCUGUU 76 AACAGGGUGGACACUGUGC 184 [844-862] 3'UTR

CCAGCUCCUCCAAGGCUCU 77 AGAGCCUUGGAGGAGCUGG 185 Rh [707-725] ORF

CUGUUGUUGCUGUGGCUGA 78 UCAGCCACAGCAACAACAG 186 Rh [225-243] ORF

UCUUCCGGACAAUGAAAUA 79 UAUUUCAUUGUCCGGAAGA 187 [877-895] 3'UTR

GCUCCCUGGAACAGCCUGA 80 UCAGGCUGUUCCAGGGAGC 188 [567-585] ORF

AUAAAGGGUUCCAAGCCUU 81 AAGGCUUGGAACCCUUUAU 189 [397-415] ORF

GAGUGGAAGCUGAAGCCUG 82 CAGGCUUCAGCUUCCACUC 190 Rh [826-844] 3'UTR

CAAACUGCAGAGUGGCACU 83 AGUGCCACUCUGCAGUUUG 191 Rh [671-689] ORF

CGGCCUUCUGCAAUUCCGA 84 UCGGAAUUGCAGAAGGCCG 192 Rh [289-307] ORF

CUCCUCCAAGGCUCUGAAA 85 UUUCAGAGCCUUGGAGGAG 193 Rh [711-729] ORF

CCUGCAAACUGCAGAGUGG 86 CCACUCUGCAGUUUGCAGG 194 Rh,Dg [667-685] ORF

CACAUCACUACCUGCAGUU 87 AACUGCAGGUAGUGAUGUG 195 [543-561] ORF

UGCCCGGAGUGGAAGCUGA 88 UCAGCUUCCACUCCGGGCA 196 [820-838] 3'UTR

GCUUCUGGCAUCCUGUUGU 89 ACAACAGGAUGCCAGAAGC 197 [213-231] ORF

UUUCUUCCGGACAAUGAAA 90 UUUCAUUGUCCGGAAGAAA 198 [875-893] 3'UTR

UGCACAGUGUCCACCCUGU 91 ACAGGGUGGACACUGUGCA 199 [843-861] 3'UTR

GACCUACACUGUUGGCUGU 92 ACAGCCAACAGUGUAGGUC 200 Rh [614-632] ORF

CACAGACGGCCUUCUGCAA 93 UUGCAGAAGGCCGUCUGUG 201 Rh [283-301] ORF

AGGGCUUCCAGUCCCGUCA 94 UGACGGGACUGGAAGCCCU 202 Rh [730-748] ORF

CCCAGAUAGCCUGAAUCCU 95 AGGAUUCAGGCUAUCUGGG 203 [802-820] ORF+3'UTR

GUUGUUGCUGUGGCUGAUA 96 UAUCAGCCACAGCAACAAC 204 Rh [227-245] ORF

GUCCCUGCGGUCCCAGAUA 97 UAUCUGGGACCGCAGGGAC 205 [791-809] ORF

CUUCCAGUCCCGUCACCUU 98 AAGGUGACGGGACUGGAAG 206 Rh [734-752] ORF

CCUACACUGUUGGCUGUGA 99 UCACAGCCAACAGUGUAGG 207 Rh [616-634] ORF

ACAUCACUACCUGCAGUUU 100 AAACUGCAGGUAGUGAUGU 208 [544-562] ORF

UCUUUCUUCCGGACAAUGA 101 UCAUUGUCCGGAAGAAAGA 209 [873-891] 3'UTR

CCAGAUAGCCUGAAUCCUG 102 CAGGAUUCAGGCUAUCUGG 210 [803-821] ORF+3'UTR

CAGUGUUUCCCUGUUUAUC 103 GAUAAACAGGGAAACACUG 211 Rh,M [643-661] ORF

CUGGCUUCUGGCAUCCUGU 104 ACAGGAUGCCAGAAGCCAG 212 [210-228] ORF

GACGGACCAGCUCCUCCAA 105 UUGGAGGAGCUGGUCCGUC 213 Rh [701-719] ORF 86 UGUUGUUGCUGUGGCUGAU 106 AUCAGCCACAGCAACAACA 214 h [226-244] ORF

87 GACUCUUGCACAUCACUAC 107 GUAGUGAUGUGCAAGAGUC 215 [535-553] ORF

88 CCCGCCAUGGAGAGUGUCU 108 AGACACUCUCCAUGGCGGG 216 Rh [450-468] ORF

89 CGAGGAGUUUCUCAUUGCU 109 AGCAAUGAGAAACUCCUCG 217 Rh [500-518] ORF

90 CACAGGUCCCACAACCGCA 110 UGCGGUUGUGGGACCUGUG 218 Rh [480-498] ORF

91 ACACCAGAAGUCAACCAGA 111 UCUGGUUGACUUCUGGUGU 219 Rh [336-354] ORF

92 UGUUCCCACUCCCAUCUUU 112 AAAGAUGGGAGUGGGAACA 220 Rh [859-877] 3'UTR

93 CCCUGUUCCCACUCCCAUC 113 GAUGGGAGUGGGAACAGGG 221 Rh [856-874] 3'UTR

94 CACCUUAUACCAGCGUUAU 114 AUAACGCUGGUAUAAGGUG 222 Rh,Rt,M [356-374] ORF

95 CACCAGAAGUCAACCAGAC 115 GUCUGGUUGACUUCUGGUG 223 Rh [337-355] ORF

96 UCCUCCAAGGCUCUGAAAA 116 UUUUCAGAGCCUUGGAGGA 224 Rh [712-730] ORF

97 GAAGCCUGCACAGUGUCCA 117 UGGACACUGUGCAGGCUUC 225 [837-855] 3'UTR

98 CCUGCACAGUGUCCACCCU 118 AGGGUGGACACUGUGCAGG 226 [841-859] 3'UTR

99 CCGCCAUGGAGAGUGUCUG 119 CAGACACUCUCCAUGGCGG 227 Rh [451-469] ORF

100 UAAAGGGUUCCAAGCCUUA 120 UAAGGCUUGGAACCCUUUA 228 [398-416] ORF

101 CAAGAUGACCAAGAUGUAU 121 AUACAUCUUGGUCAUCUUG 229 Rh [380-398] ORF

102 GUUUUGUGGCUCCCUGGAA 122 UUCCAGGGAGCCACAAAAC 230 [559-577] ORF

103 GGAGUGGAAGCUGAAGCCU 123 AGGCUUCAGCUUCCACUCC 231 Rh [825-843] 3'UTR

104 CUGACAUCCGGUUCGUCUA 124 UAGACGAACCGGAUGUCAG 232 Rh [427-445] ORF

105 GCGUUAUGAGAUCAAGAUG 125 CAUCUUGAUCUCAUAACGC 233 Rh,Dg,Rt [368-386] ORF

106 CGGACCAGCUCCUCCAAGG 126 CCUUGGAGGAGCUGGUCCG 234 Rh [703-721] ORF

107 CAGGAUGGACUCUUGCACA 127 UGUGCAAGAGUCCAUCCUG 235 [528-546] ORF

108 CAAGAUGUAUAAAGGGUUC 128 GAACCCUUUAUACAUCUUG 236 Rh [389-407] ORF

Table A2 19-mer Cross-Species siTIMPl

No. Sense (5'>3') SEQ Antisense (5'>3') SEQ Other Sp human-73858576

ID ID ORF: 193-816

NO. NO.

1 ACCACCUUAUACCAGCGUU 237 AACGCUGGUAUAAGGUGGU 252 Rh,Rt,M [354-372] ORF

2 ACCGCAGCGAGGAGUUUCU 238 AGAAACUCCUCGCUGCGGU 253 Rh,Rb,Dg,Rt [493-511] ORF

3 AGACCACCUUAUACCAGCG 239 CGCUGGUAUAAGGUGGUCU 254 Rh,Rt,M [352-370] ORF

4 GGGCUUCACCAAGACCUAC 240 GUAGGUCUUGGUGAAGCCC 255 Rh,Rb,Dg [602-620] ORF

5 CAACCGCAGCGAGGAGUUU 241 AAACUCCUCGCUGCGGUUG 256 Rh,Rb,Dg,Rt [491-509] ORF

6 CAGACCACCUUAUACCAGC 242 GCUGGUAUAAGGUGGUCUG 257 Rh,Rt,M [351-369] ORF

7 ACCUUAUACCAGCGUUAUG 243 CAUAACGCUGGUAUAAGGU 258 Rh,Rt,M [357-375] ORF

8 CGUCAUCAGGGCCAAGUUC 244 GAACUUGGCCCUGAUGACG 259 Rh,Rb,Dg [311-329] ORF

9 AUGCACAGUGUUUCCCUGU 245 ACAGGGAAACACUGUGCAU 260 Rh,Rt,M [638-656] ORF

10 ACCUGGCAGUCCCUGCGGU 246 ACCGCAGGGACUGCCAGGU 261 Rh,Rb,Dg [783-801] ORF

11 GACCACCUUAUACCAGCGU 247 ACGCUGGUAUAAGGUGGUC 262 Rh,Rt,M [353-371] ORF

12 CCGCAGCGAGGAGUUUCUC 248 GAGAAACUCCUCGCUGCGG 263 Rh,Rb,Dg,Rt [494-512] ORF

13 AACCGCAGCGAGGAGUUUC 249 GAAACUCCUCGCUGCGGUU 264 Rh,Rb,Dg,Rt [492-510] ORF

14 UUAUGAGAUCAAGAUGACC 250 GGUCAUCUUGAUCUCAUAA 265 Rh,Dg,Rt [371-389] ORF

15 ACCAGCGUUAUGAGAUCAA 251 UUGAUCUCAUAACGCUGGU 266 Rh,Rt [364-382] ORF Table A3 Preferred 19-mer siTIMPl

Table A4 19-mer siTIMPl with lowest predicted OT effect siTIMPl p21 H/ t 3 ACCAGCGUUAUGAGAUCAA 274 UUGAUCUCAUAACGCUGGU 306 siTIMPl p23 H/Rt 3 CAACCGCAGCGAGGAGUUU 275 AAACUCCUCGCUGCGGUUG 307 siTIMPl p29 Other (w/o Rt) 3 CCAGAAGUCAACCAGACCA 278 UGGUCUGGUUGACUUCUGG 310 siTIMPl_p33 Other (w/o Rt) 4 CCUGCAAACUGCAGAGUGG 280 CCACUCUGCAGUUUGCAGG 312 siTIMPl_p38 H/Rt (Rt Cross 3 CACAGUGUUUCCCUGUUUA 281 UAAACAGGGAAACACUGUG 313

- with 1MM)

siTIMPl p42 Other (w/o Rt) 3 ACAGUGUUUCCCUGUUUAU 282 AUAAACAGGGAAACACUGU 314 siTIMPl p43 Other (w/o Rt) 3 CAGUGUUUCCCUGUUUAUC 283 GAUAAACAGGGAAACACUG 315 siTIMPl p45 H +/- Rh 4 CUUUCUUCCGGACAAUGAA 284 UUCAUUGUCCGGAAGAAAG 316 siTIMPl p60 H +/- Rh 2 CAUCUUUCUUCCGGACAAU 286 AUUGUCCGGAAGAAAGAUG 318 siTIMPl p71 H +/- Rh 4 CUCCCAUCUUUCUUCCGGA 287 UCCGGAAGAAAGAUGGGAG 319 siTIMPl p73 H +/- Rh 3 GUGUUUCCCUGUUUAUCCA 288 UGGAUAAACAGGGAAACAC 320 siTIMPl p78 H +/- Rh 3 CAUGGAGAGUGUCUGCGGA 290 UCCGCAGACACUCUCCAUG 322 siTIMPl p79 H +/- Rh 3 CCAAGAUGUAUAAAGGGUU 291 AACCCUUUAUACAUCUUGG 323 siTIMPl p85 H +/- Rh 2 GAGAGUGUCUGCGGAUACU 292 AGUAUCCGCAGACACUCUC 324 siTIMPl p89 H +/- Rh 3 CUGCAGAGUGGCACUCAUU 293 AAUGAGUGCCACUCUGCAG 325 siTIMPl p91 H +/- Rh 4 CCUGGAACAGCCUGAGCUU 294 AAGCUCAGGCUGUUCCAGG 326 siTIMPl p96 H +/- Rh 4 CACUGUUGGCUGUGAGGAA 295 UUCCUCACAGCCAACAGUG 327 siTIMPl p98 H +/- Rh 3 GAUGGACUCUUGCACAUCA 296 UGAUGUGCAAGAGUCCAUC 328 siTIMPl p99 H +/- Rh 4 AGUUUCUCAUUGCUGGAAA 297 UUUCCAGCAAUGAGAAACU 329 siTIMPl pl08 H +/- Rh 2 GUCUGCGGAUACUUCCACA 298 UGUGGAAGUAUCCGCAGAC 330

Table A5 18 -mer siTIMPl

GAGGAAUGCACAGUGUUU 355 AAACACUGUGCAUUCCUC 606 R [633-650] ORF

CCAAGAUGUAUAAAGGGU 356 ACCCUUUAUACAUCUUGG 607 R [388-405] ORF

CAGACCACCUUAUACCAG 357 CUGGUAUAAGGUGGUCUG 608 Rh,Rt,Ms [351-368] ORF

AGUGGAAGCUGAAGCCUG 358 CAGGCUUCAGCUUCCACU 609 Rh [827-844] 3'UTR

ACAGUGUUUCCCUGUUUA 359 UAAACAGGGAAACACUGU 610 Rh,Ms [642-659] ORF

CGCCAUGGAGAGUGUCUG 360 CAGACACUCUCCAUGGCG 611 Rh [452-469] ORF

CACCAGAAGUCAACCAGA 361 UCUGGUUGACUUCUGGUG 612 Rh [337-354] ORF

CAGAAGUCAACCAGACCA 362 UGGUCUGGUUGACUUCUG 613 Rh [340-357] ORF

CCCACUCCCAUCUUUCUU 363 AAGAAAGAUGGGAGUGGG 614 Rh [863-880] 3'UTR

GCGAGGAGUUUCUCAUUG 364 CAAUGAGAAACUCCUCGC 615 Rh [499-516] ORF

GCUUCACCAAGACCUACA 365 UGUAGGUCUUGGUGAAGC 616 Rh [604-621] ORF

CAUCACUACCUGCAGUUU 366 AAACUGCAGGUAGUGAUG 617 [545-562] ORF

AGCGUUAUGAGAUCAAGA 367 UCUUGAUCUCAUAACGCU 618 Rh,Dg,Rt [367-384] ORF

CUGCAGAGUGGCACUCAU 368 AUGAGUGCCACUCUGCAG 619 Rh [675-692] ORF

GAAGCUGAAGCCUGCACA 369 UGUGCAGGCUUCAGCUUC 620 [831-848] 3'UTR

AUCACUACCUGCAGUUUU 370 AAAACUGCAGGUAGUGAU 621 [546-563] ORF

GCACAGUGUUUCCCUGUU 371 AACAGGGAAACACUGUGC 622 Rh,Rt,Ms [640-657] ORF

CCUGGAACAGCCUGAGCU 372 AGCUCAGGCUGUUCCAGG 623 [571-588] ORF

GCAUCCUGUUGUUGCUGU 373 ACAGCAACAACAGGAUGC 624 Rh [220-237] ORF

GUCCCAGAUAGCCUGAAU 374 AUUCAGGCUAUCUGGGAC 625 [800-817] ORF+3'UTR

AGUGUUUCCCUGUUUAUC 375 GAUAAACAGGGAAACACU 626 Rh,Ms [644-661] ORF

GGCUGUGAGGAAUGCACA 376 UGUGCAUUCCUCACAGCC 627 Rh [627-644] ORF

AGACCACCUUAUACCAGC 377 GCUGGUAUAAGGUGGUCU 628 Rh,Rt,Ms [352-369] ORF

GGAUGGACUCUUGCACAU 378 AUGUGCAAGAGUCCAUCC 629 [530-547] ORF

CGGACCAGCUCCUCCAAG 379 CUUGGAGGAGCUGGUCCG 630 Rh [703-720] ORF

GGCCUUCUGCAAUUCCGA 380 UCGGAAUUGCAGAAGGCC 631 Rh [290-307] ORF

GGGCUUCCAGUCCCGUCA 381 UGACGGGACUGGAAGCCC 632 Rh [731-748] ORF

GCAGAGUGGCACUCAUUG 382 CAAUGAGUGCCACUCUGC 633 Rh [677-694] ORF

CAGCGAGGAGUUUCUCAU 383 AUGAGAAACUCCUCGCUG 634 Rh,Rb,Rt [497-514] ORF

CAGAUAGCCUGAAUCCUG 384 CAGGAUUCAGGCUAUCUG 635 [804-821] ORF+3'UTR

GCAGCGAGGAGUUUCUCA 385 UGAGAAACUCCUCGCUGC 636 Rh,Rb,Rt [496-513] ORF

CCUGCAGUUUUGUGGCUC 386 GAGCCACAAAACUGCAGG 637 [553-570] ORF

GUUAUGAGAUCAAGAUGA 387 UCAUCUUGAUCUCAUAAC 638 Rh,Dg,Rt [370-387] ORF

CAAGAUGUAUAAAGGGUU 388 AACCCUUUAUACAUCUUG 639 Rh [389-406] ORF

CCGGAGUGGAAGCUGAAG 389 CUUCAGCUUCCACUCCGG 640 Rh [823-840] 3'UTR

AGGAGUUUCUCAUUGCUG 390 CAGCAAUGAGAAACUCCU 641 Rh [502-519] ORF

GGCUGUGCACCUGGCAGU 391 ACUGCCAGGUGCACAGCC 642 Rh [775-792] ORF

GUUUCCCUGUUUAUCCAU 392 AUGGAUAAACAGGGAAAC 643 Rh [647-664] ORF

GCAGUUUUGUGGCUCCCU 393 AGGGAGCCACAAAACUGC 644 [556-573] ORF

GUCAACCAGACCACCUUA 394 UAAGGUGGUCUGGUUGAC 645 Rh [345-362] ORF

CCAUGGAGAGUGUCUGCG 395 CGCAGACACUCUCCAUGG 646 Rh [454-471] ORF

CUGGCAUCCUGUUGUUGC 396 GCAACAACAGGAUGCCAG 647 [217-234] ORF

CAGACGGCCUUCUGCAAU 397 AUUGCAGAAGGCCGUCUG 648 Rh [285-302] ORF

ACUGCAGAGUGGCACUCA 398 UGAGUGCCACUCUGCAGU 649 Rh [674-691] ORF

CGGAGUGGAAGCUGAAGC 399 GCUUCAGCUUCCACUCCG 650 Rh [824-841] 3'UTR

GCCUCGGGAGCCAGGGCU 400 AGCCCUGGCUCCCGAGGC 651 Rh [761-778] ORF

CCAGACCACCUUAUACCA 401 UGGUAUAAGGUGGUCUGG 652 Rh [350-367] ORF

GGCUCUGAAAAGGGCUUC 402 GAAGCCCUUUUCAGAGCC 653 Rh [720-737] ORF

GCUGGAAAACUGCAGGAU 403 AUCCUGCAGUUUUCCAGC 654 [516-533] ORF

CCUGAAUCCUGCCCGGAG 404 CUCCGGGCAGGAUUCAGG 655 [811-828] ORF+3'UTR

CUGAAGCCUGCACAGUGU 405 ACACUGUGCAGGCUUCAG 656 [835-852] 3'UTR 76 GGCAUCCUGUUGUUGCUG 406 CAGCAACAACAGGAUGCC 657 R [219-236] ORF

77 CCCUGCAAACUGCAGAGU 407 ACUCUGCAGUUUGCAGGG 658 R ,Dg [666-683] ORF

78 CUGGAAAACUGCAGGAUG 408 CAUCCUGCAGUUUUCCAG 659 [517-534] ORF

79 UCUCAUUGCUGGAAAACU 409 AGUUUUCCAGCAAUGAGA 660 Rh [509-526] ORF

80 GUGGCUCCCUGGAACAGC 410 GCUGUUCCAGGGAGCCAC 661 [564-581] ORF

81 CCAGCUCCUCCAAGGCUC 411 GAGCCUUGGAGGAGCUGG 662 Rh [707-724] ORF

82 AGACCUACACUGUUGGCU 412 AGCCAACAGUGUAGGUCU 663 Rh [613-630] ORF

83 GGGACACCAGAAGUCAAC 413 GUUGACUUCUGGUGUCCC 664 Rh [333-350] ORF

84 GGCUCCCUGGAACAGCCU 414 AGGCUGUUCCAGGGAGCC 665 [566-583] ORF

85 GUUCCCACUCCCAUCUUU 415 AAAGAUGGGAGUGGGAAC 666 Rh [860-877] 3'UTR

86 CUCUGAAAAGGGCUUCCA 416 UGGAAGCCCUUUUCAGAG 667 Rh [722-739] ORF

87 GGCUUCUGGCAUCCUGUU 417 AACAGGAUGCCAGAAGCC 668 [212-229] ORF

88 AGGAAUGCACAGUGUUUC 418 GAAACACUGUGCAUUCCU 669 Rh [634-651] ORF

89 CUUCUGGCAUCCUGUUGU 419 ACAACAGGAUGCCAGAAG 670 [214-231] ORF

90 CAAACUGCAGAGUGGCAC 420 GUGCCACUCUGCAGUUUG 671 Rh [671-688] ORF

91 AUACCAGCGUUAUGAGAU 421 AUCUCAUAACGCUGGUAU 672 Rh,Rt [362-379] ORF

92 AGAGUGUCUGCGGAUACU 422 AGUAUCCGCAGACACUCU 673 Rh [460-477] ORF

93 CACCAAGACCUACACUGU 423 ACAGUGUAGGUCUUGGUG 674 Rh [608-625] ORF

94 GAUCAAGAUGACCAAGAU 424 AUCUUGGUCAUCUUGAUC 675 Rh,Dg [377-394] ORF

95 AUGUAUAAAGGGUUCCAA 425 UUGGAACCCUUUAUACAU 676 [393-410] ORF

96 ACCAAGACCUACACUGUU 426 AACAGUGUAGGUCUUGGU 677 Rh [609-626] ORF

97 CCGUCACCUUGCCUGCCU 427 AGGCAGGCAAGGUGACGG 678 Rh [743-760] ORF

98 GGGAGCCAGGGCUGUGCA 428 UGCACAGCCCUGGCUCCC 679 Rh [766-783] ORF

99 UGCACAGUGUUUCCCUGU 429 ACAGGGAAACACUGUGCA 680 Rh,Rt,Ms [639-656] ORF

100 UGCAGAGUGGCACUCAUU 430 AAUGAGUGCCACUCUGCA 681 Rh [676-693] ORF

101 GUGAGGAAUGCACAGUGU 431 ACACUGUGCAUUCCUCAC 682 Rh [631-648] ORF

102 AGCGAGGAGUUUCUCAUU 432 AAUGAGAAACUCCUCGCU 683 Rh [498-515] ORF

103 GGGCUGUGCACCUGGCAG 433 CUGCCAGGUGCACAGCCC 684 Rh [774-791] ORF

104 ACUCAUUGCUUGUGGACG 434 CGUCCACAAGCAAUGAGU 685 Rh [687-704] ORF

105 UGUUGUUGCUGUGGCUGA 435 UCAGCCACAGCAACAACA 686 Rh [226-243] ORF

106 UGAGGAAUGCACAGUGUU 436 AACACUGUGCAUUCCUCA 687 Rh [632-649] ORF

107 CCUGGCUUCUGGCAUCCU 437 AGGAUGCCAGAAGCCAGG 688 [209-226] ORF

108 GCACAGUGUCCACCCUGU 438 ACAGGGUGGACACUGUGC 689 [844-861] 3'UTR

109 AAAGGGUUCCAAGCCUUA 439 UAAGGCUUGGAACCCUUU 690 [399-416] ORF

110 GCUUCUGGCAUCCUGUUG 440 CAACAGGAUGCCAGAAGC 691 [213-230] ORF

111 CCAAGACCUACACUGUUG 441 CAACAGUGUAGGUCUUGG 692 Rh [610-627] ORF

112 AAGGGUUCCAAGCCUUAG 442 CUAAGGCUUGGAACCCUU 693 [400-417] ORF

113 UGCACAGUGUCCACCCUG 443 CAGGGUGGACACUGUGCA 694 [843-860] 3'UTR

114 GACCUACACUGUUGGCUG 444 CAGCCAACAGUGUAGGUC 695 Rh [614-631] ORF

115 CCCAGAUAGCCUGAAUCC 445 GGAUUCAGGCUAUCUGGG 696 [802-819] ORF+3'UTR

116 GGGUUCCAAGCCUUAGGG 446 CCCUAAGGCUUGGAACCC 697 [402-419] ORF

117 GGCUUCCAGUCCCGUCAC 447 GUGACGGGACUGGAAGCC 698 Rh [732-749] ORF

118 AGUGUCUGCGGAUACUUC 448 GAAGUAUCCGCAGACACU 699 Rh [462-479] ORF

119 UGACCAAGAUGUAUAAAG 449 CUUUAUACAUCUUGGUCA 700 Rh [385-402] ORF

120 CAGCCUGAGCUUAGCUCA 450 UGAGCUAAGCUCAGGCUG 701 [578-595] ORF

121 CUUCCGGACAAUGAAAUA 451 UAUUUCAUUGUCCGGAAG 702 [878-895] 3'UTR

122 CUGUGAGGAAUGCACAGU 452 ACUGUGCAUUCCUCACAG 703 Rh [629-646] ORF

123 GCCUGAAUCCUGCCCGGA 453 UCCGGGCAGGAUUCAGGC 704 [810-827] ORF+3'UTR

124 ACUGCAGGAUGGACUCUU 454 AAGAGUCCAUCCUGCAGU 705 [524-541] ORF

125 GUCCCACAACCGCAGCGA 455 UCGCUGCGGUUGUGGGAC 706 Rh [485-502] ORF 126 AUCUUUCUUCCGGACAAU 456 AUUGUCCGGAAGAAAGAU 707 [872-889] 3'UTR

127 AUAAAGGGUUCCAAGCCU 457 AGGCUUGGAACCCUUUAU 708 [397-414] ORF

128 UCCCAUCUUUCUUCCGGA 458 UCCGGAAGAAAGAUGGGA 709 [868-885] 3'UTR

129 GAAAAGGGCUUCCAGUCC 459 GGACUGGAAGCCCUUUUC 710 h [726-743] ORF

130 UGGAACAGCCUGAGCUUA 460 UAAGCUCAGGCUGUUCCA 711 [573-590] ORF

131 CACCUUAUACCAGCGUUA 461 UAACGCUGGUAUAAGGUG 712 Rh,Rt,Ms [356-373] ORF

132 CUGUUGGCUGUGAGGAAU 462 AUUCCUCACAGCCAACAG 713 Rh [622-639] ORF

133 GCACAUCACUACCUGCAG 463 CUGCAGGUAGUGAUGUGC 714 [542-559] ORF

134 UGCUGUGGCUGAUAGCCC 464 GGGCUAUCAGCCACAGCA 715 Rh [232-249] ORF

135 CCACUCCCAUCUUUCUUC 465 GAAGAAAGAUGGGAGUGG 716 Rh [864-881] 3'UTR

136 CUGGCUUCUGGCAUCCUG 466 CAGGAUGCCAGAAGCCAG 717 [210-227] ORF

137 CUUCCACAGGUCCCACAA 467 UUGUGGGACCUGUGGAAG 718 Rh [476-493] ORF

138 ACCAGCUCCUCCAAGGCU 468 AGCCUUGGAGGAGCUGGU 719 Rh [706-723] ORF

139 CAAGAUGACCAAGAUGUA 469 UACAUCUUGGUCAUCUUG 720 Rh [380-397] ORF

140 CCCGCCAUGGAGAGUGUC 470 GACACUCUCCAUGGCGGG 721 Rh [450-467] ORF

141 CCCGGAGUGGAAGCUGAA 471 UUCAGCUUCCACUCCGGG 722 Rh [822-839] 3'UTR

142 CGAGGAGUUUCUCAUUGC 472 GCAAUGAGAAACUCCUCG 723 Rh [500-517] ORF

143 CACAUCACUACCUGCAGU 473 ACUGCAGGUAGUGAUGUG 724 [543-560] ORF

144 CUCCAAGGCUCUGAAAAG 474 CUUUUCAGAGCCUUGGAG 725 Rh [714-731] ORF

145 UGAGAUCAAGAUGACCAA 475 UUGGUCAUCUUGAUCUCA 726 Rh,Dg [374-391] ORF

146 GCACUCAUUGCUUGUGGA 476 UCCACAAGCAAUGAGUGC 727 Rh,Rb [685-702] ORF

147 CAUUGCUUGUGGACGGAC 477 GUCCGUCCACAAGCAAUG 728 Rh [690-707] ORF

148 GGACCAGCUCCUCCAAGG 478 CCUUGGAGGAGCUGGUCC 729 Rh [704-721] ORF

149 GCCUGCACAGUGUCCACC 479 GGUGGACACUGUGCAGGC 730 [840-857] 3'UTR

150 UGUAUAAAGGGUUCCAAG 480 CUUGGAACCCUUUAUACA 731 [394-411] ORF

151 CCUGCACAGUGUCCACCC 481 GGGUGGACACUGUGCAGG 732 [841-858] 3'UTR

152 ACCUUAUACCAGCGUUAU 482 AUAACGCUGGUAUAAGGU 733 Rh,Rt,Ms [357-374] ORF

153 CUUCCAGUCCCGUCACCU 483 AGGUGACGGGACUGGAAG 734 Rh [734-751] ORF

154 CAGUGUCCACCCUGUUCC 484 GGAACAGGGUGGACACUG 735 [847-864] 3'UTR

155 GGAGUGGAAGCUGAAGCC 485 GGCUUCAGCUUCCACUCC 736 Rh [825-842] 3'UTR

156 CUUAUACCAGCGUUAUGA 486 UCAUAACGCUGGUAUAAG 737 Rh,Rt [359-376] ORF

157 CCGCAGCGAGGAGUUUCU 487 AGAAACUCCUCGCUGCGG 738 Rh,Rb,Dg,Rt [494-511] ORF

158 CAGUUUUGUGGCUCCCUG 488 CAGGGAGCCACAAAACUG 739 [557-574] ORF

159 GUAUAAAGGGUUCCAAGC 489 GCUUGGAACCCUUUAUAC 740 [395-412] ORF

160 AAGCCUGCACAGUGUCCA 490 UGGACACUGUGCAGGCUU 741 [838-855] 3'UTR

161 AGGAUGGACUCUUGCACA 491 UGUGCAAGAGUCCAUCCU 742 [529-546] ORF

162 AUGGAGAGUGUCUGCGGA 492 UCCGCAGACACUCUCCAU 743 Rh [456-473] ORF

163 GCCUUCUGCAAUUCCGAC 493 GUCGGAAUUGCAGAAGGC 744 Rh [291-308] ORF

164 CUUCUGCAAUUCCGACCU 494 AGGUCGGAAUUGCAGAAG 745 Rh [293-310] ORF

165 AGACGGCCUUCUGCAAUU 495 AAUUGCAGAAGGCCGUCU 746 Rh [286-303] ORF

166 GCAGGAUGGACUCUUGCA 496 UGCAAGAGUCCAUCCUGC 747 [527-544] ORF

167 GCUUGUGGACGGACCAGC 497 GCUGGUCCGUCCACAAGC 748 Rh [694-711] ORF

168 AGAAGUCAACCAGACCAC 498 GUGGUCUGGUUGACUUCU 749 Rh [341-358] ORF

169 CUGUGCACCUGGCAGUCC 499 GGACUGCCAGGUGCACAG 750 Rh [777-794] ORF

170 GAGGAGUUUCUCAUUGCU 500 AGCAAUGAGAAACUCCUC 751 Rh [501-518] ORF

171 UGUUCCCACUCCCAUCUU 501 AAGAUGGGAGUGGGAACA 752 Rh [859-876] 3'UTR

172 ACCGCAGCGAGGAGUUUC 502 GAAACUCCUCGCUGCGGU 753 Rh,Rb,Dg,Rt [493-510] ORF

173 ACCAGAAGUCAACCAGAC 503 GUCUGGUUGACUUCUGGU 754 Rh [338-355] ORF

174 GCAAUUCCGACCUCGUCA 504 UGACGAGGUCGGAAUUGC 755 Rh [298-315] ORF

175 CUGCAAACUGCAGAGUGG 505 CCACUCUGCAGUUUGCAG 756 Rh [668-685] ORF

176 GGAGCCAGGGCUGUGCAC 506 GUGCACAGCCCUGGCUCC 757 Rh [767-784] ORF 177 CCUUCUGCAAUUCCGACC 507 GGUCGGAAUUGCAGAAGG 758 R [292-309] ORF

178 CUUGCACAUCACUACCUG 508 CAGGUAGUGAUGUGCAAG 759 [539-556] ORF

179 GGAAAACUGCAGGAUGGA 509 UCCAUCCUGCAGUUUUCC 760 [519-536] ORF

180 AAUGCACAGUGUUUCCCU 510 AGGGAAACACUGUGCAUU 761 R [637-654] ORF

181 CCCUGGAACAGCCUGAGC 511 GCUCAGGCUGUUCCAGGG 762 [570-587] ORF

182 GGAUGCCGCUGACAUCCG 512 CGGAUGUCAGCGGCAUCC 763 Rh [419-436] ORF

183 GGAUACUUCCACAGGUCC 513 GGACCUGUGGAAGUAUCC 764 Rh [471-488] ORF

184 CACUCAUUGCUUGUGGAC 514 GUCCACAAGCAAUGAGUG 765 Rh,Rb [686-703] ORF

185 GACACCAGAAGUCAACCA 515 UGGUUGACUUCUGGUGUC 766 Rh [335-352] ORF

186 CUACACUGUUGGCUGUGA 516 UCACAGCCAACAGUGUAG 767 Rh [617-634] ORF

187 ACCACCUUAUACCAGCGU 517 ACGCUGGUAUAAGGUGGU 768 Rh,Rt,Ms [354-371] ORF

188 AGAGUGGCACUCAUUGCU 518 AGCAAUGAGUGCCACUCU 769 Rh [679-696] ORF

189 GCAAACUGCAGAGUGGCA 519 UGCCACUCUGCAGUUUGC 770 Rh [670-687] ORF

190 GCCGCUGACAUCCGGUUC 520 GAACCGGAUGUCAGCGGC 771 Rh [423-440] ORF

191 UGUUUCCCUGUUUAUCCA 521 UGGAUAAACAGGGAAACA 772 Rh [646-663] ORF

192 AAGUCAACCAGACCACCU 522 AGGUGGUCUGGUUGACUU 773 Rh [343-360] ORF

193 CCACAACCGCAGCGAGGA 523 UCCUCGCUGCGGUUGUGG 774 Rh [488-505] ORF

194 GCCUGAGCUUAGCUCAGC 524 GCUGAGCUAAGCUCAGGC 775 [580-597] ORF

195 GUCAUCAGGGCCAAGUUC 525 GAACUUGGCCCUGAUGAC 776 Rh,Dg [312-329] ORF

196 AACCAGACCACCUUAUAC 526 GUAUAAGGUGGUCUGGUU 777 Rh [348-365] ORF

197 CUCCCUGGAACAGCCUGA 527 UCAGGCUGUUCCAGGGAG 778 [568-585] ORF

198 CCAAGGCUCUGAAAAGGG 528 CCCUUUUCAGAGCCUUGG 779 Rh [716-733] ORF

199 CUCAUUGCUGGAAAACUG 529 CAGUUUUCCAGCAAUGAG 780 Rh [510-527] ORF

200 GUGUCCACCCUGUUCCCA 530 UGGGAACAGGGUGGACAC 781 [849-866] 3'UTR

201 CCUGUUCCCACUCCCAUC 531 GAUGGGAGUGGGAACAGG 782 Rh [857-874] 3'UTR

202 CACCUUGCCUGCCUGCCU 532 AGGCAGGCAGGCAAGGUG 783 Rh [747-764] ORF

203 UCACCAAGACCUACACUG 533 CAGUGUAGGUCUUGGUGA 784 Rh [607-624] ORF

204 GAAUGCACAGUGUUUCCC 534 GGGAAACACUGUGCAUUC 785 Rh [636-653] ORF

205 AUGGACUCUUGCACAUCA 535 UGAUGUGCAAGAGUCCAU 786 [532-549] ORF

206 UGUGAGGAAUGCACAGUG 536 CACUGUGCAUUCCUCACA 787 Rh [630-647] ORF

207 GAGCCAGGGCUGUGCACC 537 GGUGCACAGCCCUGGCUC 788 Rh [768-785] ORF

208 UGCGGUCCCAGAUAGCCU 538 AGGCUAUCUGGGACCGCA 789 [796-813] ORF

209 CUGUUCCCACUCCCAUCU 539 AGAUGGGAGUGGGAACAG 790 Rh [858-875] 3'UTR

210 UGGCUUCUGGCAUCCUGU 540 ACAGGAUGCCAGAAGCCA 791 [211-228] ORF

211 CGGAUACUUCCACAGGUC 541 GACCUGUGGAAGUAUCCG 792 Rh [470-487] ORF

212 CACAGUGUCCACCCUGUU 542 AACAGGGUGGACACUGUG 793 [845-862] 3'UTR

213 GGAAUGCACAGUGUUUCC 543 GGAAACACUGUGCAUUCC 794 Rh [635-652] ORF

214 CCAGGGCUGUGCACCUGG 544 CCAGGUGCACAGCCCUGG 795 Rh [771-788] ORF

215 CCCUGCGGUCCCAGAUAG 545 CUAUCUGGGACCGCAGGG 796 [793-810] ORF

216 GCCUGCACCUGUGUCCCA 546 UGGGACACAGGUGCAGGC 797 Rb [258-275] ORF

217 CAGAGUGGCACUCAUUGC 547 GCAAUGAGUGCCACUCUG 798 Rh [678-695] ORF

218 UGCACAUCACUACCUGCA 548 UGCAGGUAGUGAUGUGCA 799 [541-558] ORF

219 GAAGUCAACCAGACCACC 549 GGUGGUCUGGUUGACUUC 800 Rh [342-359] ORF

220 UCCCUGCGGUCCCAGAUA 550 UAUCUGGGACCGCAGGGA 801 [792-809] ORF

221 AGUGGCACUCAUUGCUUG 551 CAAGCAAUGAGUGCCACU 802 Rh [681-698] ORF

222 GUGGCACUCAUUGCUUGU 552 ACAAGCAAUGAGUGCCAC 803 Rh [682-699] ORF

223 CUGAAUCCUGCCCGGAGU 553 ACUCCGGGCAGGAUUCAG 804 [812-829] ORF+3'UTR

224 CCUGCACCUGUGUCCCAC 554 GUGGGACACAGGUGCAGG 805 Rb [259-276] ORF

225 GCCUGCCUCGGGAGCCAG 555 CUGGCUCCCGAGGCAGGC 806 Rh [757-774] ORF

226 GGGAUGCCGCUGACAUCC 556 GGAUGUCAGCGGCAUCCC 807 Rh [418-435] ORF

227 GCACCUGGCAGUCCCUGC 557 GCAGGGACUGCCAGGUGC 808 Rh,Dg [781-798] ORF 228 UCCUGUUGUUGCUGUGGC 558 GCCACAGCAACAACAGGA 809 R [223-240] ORF

229 UGCGGAUACUUCCACAGG 559 CCUGUGGAAGUAUCCGCA 810 R [468-485] ORF

230 GACCAAGAUGUAUAAAGG 560 CCUUUAUACAUCUUGGUC 811 Rh [386-403] ORF

231 ACUGUUGGCUGUGAGGAA 561 UUCCUCACAGCCAACAGU 812 Rh [621-638] ORF

232 CAUUGCUGGAAAACUGCA 562 UGCAGUUUUCCAGCAAUG 813 Rh [512-529] ORF

233 UGAAAAGGGCUUCCAGUC 563 GACUGGAAGCCCUUUUCA 814 Rh [725-742] ORF

234 CGUCAUCAGGGCCAAGUU 564 AACUUGGCCCUGAUGACG 815 Rh,Rb,Dg [311-328] ORF

235 ACAACCGCAGCGAGGAGU 565 ACUCCUCGCUGCGGUUGU 816 Rh [490-507] ORF

236 UGUCCACCCUGUUCCCAC 566 GUGGGAACAGGGUGGACA 817 Rh [850-867] 3'UTR

237 CCUGGCAGUCCCUGCGGU 567 ACCGCAGGGACUGCCAGG 818 [784-801] ORF

238 UGAAGCCUGCACAGUGUC 568 GACACUGUGCAGGCUUCA 819 [836-853] 3'UTR

239 UCCCAGAUAGCCUGAAUC 569 GAUUCAGGCUAUCUGGGA 820 [801-818] ORF+3'UTR

240 AGCCUGAGCUUAGCUCAG 570 CUGAGCUAAGCUCAGGCU 821 [579-596] ORF

241 CACUACCUGCAGUUUUGU 571 ACAAAACUGCAGGUAGUG 822 [548-565] ORF

242 CUGCACAGUGUCCACCCU 572 AGGGUGGACACUGUGCAG 823 [842-859] 3'UTR

243 CUCGGGAGCCAGGGCUGU 573 ACAGCCCUGGCUCCCGAG 824 Rh [763-780] ORF

244 AGCCAGGGCUGUGCACCU 574 AGGUGCACAGCCCUGGCU 825 Rh [769-786] ORF

245 GCCAUGGAGAGUGUCUGC 575 GCAGACACUCUCCAUGGC 826 Rh [453-470] ORF

246 AGGGCUGUGCACCUGGCA 576 UGCCAGGUGCACAGCCCU 827 Rh [773-790] ORF

247 GAGCUUAGCUCAGCGCCG 577 CGGCGCUGAGCUAAGCUC 828 Rh [584-601] ORF

248 AGGCUCUGAAAAGGGCUU 578 AAGCCCUUUUCAGAGCCU 829 Rh [719-736] ORF

249 ACAUCACUACCUGCAGUU 579 AACUGCAGGUAGUGAUGU 830 [544-561] ORF

250 AACCGCAGCGAGGAGUUU 580 AAACUCCUCGCUGCGGUU 831 Rh,Rb,Dg,Rt [492-509] ORF

251 CAGCUCCUCCAAGGCUCU 581 AGAGCCUUGGAGGAGCUG 832 Rh [708-725] ORF

Table A6 18-mer Cross-Species siTIMPl

Table A7 Preferred 18+A-mer siTIMPl

siTIMPl pll CUUAUACCAGCGUUAUGAA 853 UUCAUAACGCUGGUAUAAG 934 18+1 [359-376] ORF siTIMPl pl2 CCGCAGCGAGGAGUUUCUA 854 UAGAAACUCCUCGCUGCGG 935 18+1 [494-511] ORF siTIMPl pl3 ACCGCAGCGAGGAGUUUCA 855 UGAAACUCCUCGCUGCGGU 936 18+1 [493-510] ORF siTIMPl pl5 ACCACCUUAUACCAGCGUA 856 UACGCUGGUAUAAGGUGGU 937 18+1 [354-371] ORF siTIMPl pl8 AACCGCAGCGAGGAGUUUA 857 UAAACUCCUCGCUGCGGUU 938 18+1 [492-509] ORF siTIMPl p22 UAUACCAGCGUUAUGAGAA 858 UUCUCAUAACGCUGGUAUA 939 18+1 [361-378] ORF siTIMPl p25 AGAUCAAGAUGACCAAGAA 859 UUCUUGGUCAUCUUGAUCU 940 18+1 [376-393] ORF siTIMPl p26 CCUGCAAACUGCAGAGUGA 860 UCACUCUGCAGUUUGCAGG 941 18+1 [667-684] ORF siTIMPl p28 CCCUGCAAACUGCAGAGUA 861 UACUCUGCAGUUUGCAGGG 942 18+1 [666-683] ORF siTIMPl p30 GAUCAAGAUGACCAAGAUA 862 UAUCUUGGUCAUCUUGAUC 943 18+1 [377-394] ORF siTIMPl p32 GUCAUCAGGGCCAAGUUCA 863 UGAACUUGGCCCUGAUGAC 944 18+1 [312-329] ORF siTIMPl p34 CCUGCACCUGUGUCCCACA 864 UGUGGGACACAGGUGCAGG 945 18+1 [259-276] ORF siTIMPl p35 GGGCUUCACCAAGACCUAA 865 UUAGGUCUUGGUGAAGCCC 946 18+1 [602-619] ORF siTIMPl p36 CGUCAUCAGGGCCAAGUUA 866 UAACUUGGCCCUGAUGACG 947 18+1 [311-328] ORF siTIMPl p37 CACUCAUUGCUUGUGGACA 867 UGUCCACAAGCAAUGAGUG 948 18+1 [686-703] ORF siTIMPl_p39 CAGUGUUUCCCUGUUUAUA 868 UAUAAACAGGGAAACACUG 949 18+1 [643-660] ORF siTIMPl p40 ACAGUGUUUCCCUGUUUAA 869 UUAAACAGGGAAACACUGU 950 18+1 [642-659] ORF siTIMPl p41 AGUGUUUCCCUGUUUAUCA 870 UGAUAAACAGGGAAACACU 951 18+1 [644-661] ORF siTIMPl p44 CAUCUUUCUUCCGGACAAA 871 UUUGUCCGGAAGAAAGAUG 952 18+1 [871-888] 3'UTR siTIMPl p46 CCAGAUAGCCUGAAUCCUA 872 UAGGAUUCAGGCUAUCUGG 953 18+1 [803-820]

ORF+3'UTR siTIMPl p47 GGUCCCAGAUAGCCUGAAA 873 UUUCAGGCUAUCUGGGACC 954 18+1 [799-816] ORF siTIMPl p48 GGAGAGUGUCUGCGGAUAA 874 UUAUCCGCAGACACUCUCC 955 18+1 [458-475] ORF siTIMPl p50 CCGCCAUGGAGAGUGUCUA 875 UAGACACUCUCCAUGGCGG 956 18+1 [458-475] ORF siTIMPl p51 GAGUGUCUGCGGAUACUUA 876 UAAGUAUCCGCAGACACUC 957 18+1 [458-475] ORF siTIMPl p52 GAGUGGCACUCAUUGCUUA 877 UAAGCAAUGAGUGCCACUC 958 18+1 [680-697] ORF siTIMPl p53 GAGUGGAAGCUGAAGCCUA 878 UAGGCUUCAGCUUCCACUC 959 18+1 [826-843] 3'UTR siTIMPl p54 CCCUGUUCCCACUCCCAUA 879 UAUGGGAGUGGGAACAGGG 960 18+1 [856-873] 3'UTR siTIMPl p55 GCGGAUACUUCCACAGGUA 880 UACCUGUGGAAGUAUCCGC 961 18+1 [469-486] ORF siTIMPl p56 GAGAGUGUCUGCGGAUACA 881 UGUAUCCGCAGACACUCUC 962 18+1 [459-476] ORF siTIMPl_p57 GGAACAGCCUGAGCUUAGA 882 UCUAAGCUCAGGCUGUUCC 963 18+1 [574-591] ORF siTIMPl p58 CAACCAGACCACCUUAUAA 883 UUAUAAGGUGGUCUGGUUG 964 18+1 [347-364] ORF siTIMPl p59 GAGGAAUGCACAGUGUUUA 884 UAAACACUGUGCAUUCCUC 965 18+1 [633-650] ORF siTIMPl p61 CCAAGAUGUAUAAAGGGUA 885 UACCCUUUAUACAUCUUGG 966 18+1 [388-405] ORF siTIMPl p62 CACCAGAAGUCAACCAGAA 886 UUCUGGUUGACUUCUGGUG 967 18+1 [337-354] ORF siTIMPl p63 CAGAAGUCAACCAGACCAA 887 UUGGUCUGGUUGACUUCUG 968 18+1 [340-357] ORF siTIMPl p64 CCCACUCCCAUCUUUCUUA 888 UAAGAAAGAUGGGAGUGGG 969 18+1 [863-880] 3'UTR siTIMPl p65 GCGAGGAGUUUCUCAUUGA 889 UCAAUGAGAAACUCCUCGC 970 18+1 [499-516] ORF siTIMPl p66 CUGCAGAGUGGCACUCAUA 890 UAUGAGUGCCACUCUGCAG 971 18+1 [675-692] ORF siTIMPl p67 GAAGCUGAAGCCUGCACAA 891 UUGUGCAGGCUUCAGCUUC 972 18+1 [831-848] 3'UTR siTIMPl p68 CCUGGAACAGCCUGAGCUA 892 UAGCUCAGGCUGUUCCAGG 973 18+1 [571-588] ORF siTIMPl p69 GCAUCCUGUUGUUGCUGUA 893 UACAGCAACAACAGGAUGC 974 18+1 [220-237] ORF siTIMPl_p70 GUCCCAGAUAGCCUGAAUA 894 UAUUCAGGCUAUCUGGGAC 975 18+1 [800-817]

ORF+3'UTR siTIMPl p72 GGCUGUGAGGAAUGCACAA 895 UUGUGCAUUCCUCACAGCC 976 18+1 [627-644] ORF siTIMPl p74 GGCCUUCUGCAAUUCCGAA 896 UUCGGAAUUGCAGAAGGCC 977 18+1 [290-307] ORF siTIMPl p75 GCAGAGUGGCACUCAUUGA 897 UCAAUGAGUGCCACUCUGC 978 18+1 [677-694] ORF siTIMPl_p76 CAGAUAGCCUGAAUCCUGA 898 UCAGGAUUCAGGCUAUCUG 979 18+1 [804-821]

ORF+3'UTR siTIMPl p80 CCGGAGUGGAAGCUGAAGA 899 UCUUCAGCUUCCACUCCGG 980 18+1 [823-840] 3'UTR siTIMPl p81 GGCUGUGCACCUGGCAGUA 900 UACUGCCAGGUGCACAGCC 981 18+1 [775-792] ORF siTIMPl p82 GUCAACCAGACCACCUUAA 901 UUAAGGUGGUCUGGUUGAC 982 18+1 [345-362] ORF siTIMPl p83 CCAUGGAGAGUGUCUGCGA 902 UCGCAGACACUCUCCAUGG 983 18+1 [454-471] ORF siTIMPl p84 CUGGCAUCCUGUUGUUGCA 903 UGCAACAACAGGAUGCCAG 984 18+1 [217-234] ORF siTIMPl p86 ACUGCAGAGUGGCACUCAA 904 UUGAGUGCCACUCUGCAGU 985 18+1 [674-691] ORF siTIMPl p87 CGGAGUGGAAGCUGAAGCA 905 UGCUUCAGCUUCCACUCCG 986 18+1 [824-841] 3'UTR siTIMPl p88 CCAGACCACCUUAUACCAA 906 UUGGUAUAAGGUGGUCUGG 987 18+1 [350-367] ORF siTIMPl _p90 GCUGGAAAACUGCAGGAUA 907 UAUCCUGCAGUUUUCCAGC 988 18+1 [516-533] ORF siTIMPl _p92 CCUGAAUCCUGCCCGGAGA 908 UCUCCGGGCAGGAUUCAGG 989 18+1 [811-828]

ORF+3'UTR siTIMPl p93 CUGAAGCCUGCACAGUGUA 909 UACACUGUGCAGGCUUCAG 990 18+1 [835-852] 3'UTR siTIMPl p94 CUGGAAAACUGCAGGAUGA 910 UCAUCCUGCAGUUUUCCAG 991 18+1 [517-534] ORF siTIMPl p95 UCUCAUUGCUGGAAAACUA 911 UAGUUUUCCAGCAAUGAGA 992 18+1 [509-526] ORF siTIMPl p97 AGACCUACACUGUUGGCUA 912 UAGCCAACAGUGUAGGUCU 993 18+1 [613-630] ORF siTIMPl plOO GGGACACCAGAAGUCAACA 913 UGUUGACUUCUGGUGUCCC 994 18+1 [333-350] ORF siTIMPl plOl GGCUCCCUGGAACAGCCUA 914 UAGGCUGUUCCAGGGAGCC 995 18+1 [566-583] ORF siTIMPl pl02 GUUCCCACUCCCAUCUUUA 915 UAAAGAUGGGAGUGGGAAC 996 18+1 [860-877] 3'UTR siTIMPl pl03 GGCUUCUGGCAUCCUGUUA 916 UAACAGGAUGCCAGAAGCC 997 18+1 [212-229] ORF siTIMPl pl04 CUUCUGGCAUCCUGUUGUA 917 UACAACAGGAUGCCAGAAG 998 18+1 [214-231] ORF siTIMPl pl05 AGAGUGUCUGCGGAUACUA 918 UAGUAUCCGCAGACACUCU 999 18+1 [460-477] ORF siTIMPl pl06 CACCAAGACCUACACUGUA 919 UACAGUGUAGGUCUUGGUG 1000 18+1 [608-625] ORF siTIMPl _pl09 GGGAGCCAGGGCUGUGCAA 920 UUGCACAGCCCUGGCUCCC 1001 18+1 [766-783] ORF siTIMPl pllO UGCAGAGUGGCACUCAUUA 921 UAAUGAGUGCCACUCUGCA 1002 18+1 [676-693] ORF siTIMPl pill GUGAGGAAUGCACAGUGUA 922 UACACUGUGCAUUCCUCAC 1003 18+1 [631-648] ORF siTIMPl pll2 AGCGAGGAGUUUCUCAUUA 923 UAAUGAGAAACUCCUCGCU 1004 18+1 [498-515] ORF siTIMPl pll3 GGGCUGUGCACCUGGCAGA 924 UCUGCCAGGUGCACAGCCC 1005 18+1 [774-791] ORF siTIMPl pll4 UGUUGUUGCUGUGGCUGAA 925 UUCAGCCACAGCAACAACA 1006 18+1 [226-243] ORF

Table A8: 18+1-mer siTIMPl with lowest predicted Off Target (OT) effect

H +/- h 3 GAGUGUCUGCGGAUACUUA 876 UAAGUAUCCGCAGACACUC 957 siTIMPl p51

H +/- Rh 3 GAGUGGCACUCAUUGCUUA 877 UAAGCAAUGAGUGCCACUC 958 siTIMPl p52

H +/- Rh 2 GCGGAUACUUCCACAGGUA 880 UACCUGUGGAAGUAUCCGC 961 siTIMPl p55

H +/- Rh 2 GAGAGUGUCUGCGGAUACA 881 UGUAUCCGCAGACACUCUC 962 siTIMPl_p56

H +/- Rh 3 CAACCAGACCACCUUAUAA 883 UUAUAAGGUGGUCUGGUUG 964 siTIMPl p58

H +/- Rh 3 CCAAGAUGUAUAAAGGGUA 885 UACCCUUUAUACAUCUUGG 966 siTIMPl p61

H +/- Rh 4 CCCACUCCCAUCUUUCUUA 888 UAAGAAAGAUGGGAGUGGG 969 siTIMPl p64

H +/- Rh 3 CUGCAGAGUGGCACUCAUA 890 UAUGAGUGCCACUCUGCAG 971 siTIMPl p66

H +/- Rh 4 CCUGGAACAGCCUGAGCUA 892 UAGCUCAGGCUGUUCCAGG 973 siTIMPl p68

H +/- Rh 3 GUCCCAGAUAGCCUGAAUA 894 UAUUCAGGCUAUCUGGGAC 975 siTIMPl p70

H +/- Rh 4 GCAGAGUGGCACUCAUUGA 897 UCAAUGAGUGCCACUCUGC 978 siTIMPl p75

H +/- Rh 3 CCAUGGAGAGUGUCUGCGA 903 UCGCAGACACUCUCCAUGG 983 siTIMPl p83

H +/- Rh 4 ACUGCAGAGUGGCACUCAA 904 UUGAGUGCCACUCUGCAGU 985 siTIMPl p86

H +/- Rh 2 CCAGACCACCUUAUACCAA 906 UUGGUAUAAGGUGGUCUGG 987 siTIMPl p88

H +/- Rh 4 CCUGAAUCCUGCCCGGAGA 908 UCUCCGGGCAGGAUUCAGG 989 siTIMPl p92

H +/- Rh 3 CUGAAGCCUGCACAGUGUA 909 UACACUGUGCAGGCUUCAG 990 siTIMPl_p93

H +/- Rh 4 UCUCAUUGCUGGAAAACUA 911 UAGUUUUCCAGCAAUGAGA 992 siTIMPl p95

H +/- Rh 2 AGACCUACACUGUUGGCUA 912 UAGCCAACAGUGUAGGUCU 993 siTIMPl p97

H +/- Rh 4 GUUCCCACUCCCAUCUUUA 915 UAAAGAUGGGAGUGGGAAC 996 siTIMPl pl02

H +/- Rh 4 CUUCUGGCAUCCUGUUGUA 917 UACAACAGGAUGCCAGAAG 998 siTIMPl pl04

H +/- Rh 2 AGAGUGUCUGCGGAUACUA 918 UAGUAUCCGCAGACACUCU 999 siTIMPl pl05

H +/- Rh 3 CACCAAGACCUACACUGUA 919 UACAGUGUAGGUCUUGGUG 1000 siTIMPl pl06

H +/- Rh 2 UGCAGAGUGGCACUCAUUA 921 UAAUGAGUGCCACUCUGCA 1002 siTIMPl pllO

H +/- Rh 4 AGCGAGGAGUUUCUCAUUA 923 UAAUGAGAAACUCCUCGCU 1004 siTIMPl pll2

TIMP2 - TIMP metallopeptidase inhibitor 2

Table Bl : siTIMP2 19 -mers

CCUGCAAGCAACUCAAAAU 1027 AUUUUGAGUUGCUUGCAGG 1642 [3343-3361] 3'UTB

GGAUAUAGAGUUUAUCUAC 1028 GUAGAUAAACUCUAUAUCC 1643 [553-571] ORF

GAUGCUUUGUAUCAUUCUU 1029 AAGAAUGAUACAAAGCAUC 1644 [3589-3607] 3'UTB

GCAAGCAACUCAAAAUAUU 1030 AAUAUUUUGAGUUGCUUGC 1645 [3346-3364] 3'UTB

CGUCUUUGGUUCUCCAGUU 1031 AACUGGAGAACCAAAGACG 1646 [3055-3073] 3'UTB

CCUUUAUAUUUGAUCCACA 1032 UGUGGAUCAAAUAUAAAGG 1647 [3127-3145] 3'UTB

GUGCUGAGCAGAAAACAAA 1033 UUUGUUUUCUGCUCAGCAC 1648 [3164-3182] 3'UTB

CCAACUUCUGCUUGUAUUU 1034 AAAUACAAGCAGAAGUUGG 1649 h [2207-2225] 3'UTB

CCUAUUAAUCCUCAGAAUU 1035 AAUUCUGAGGAUUAAUAGG 1650 Rh [1572-1590] 3'UTB

CGGUAAUGAUAAGGAGAAU 1036 AUUCUCCUUAUCAUUACCG 1651 [2345-2363] 3'UTB

CGCUCAAAUACCUUCACAA 1037 UUGUGAAGGUAUUUGAGCG 1652 [3223-3241] 3'UTB

GGGCAGACUGGGAGGGUAU 1038 AUACCCUCCCAGUCUGCCC 1653 Rh [2619-2637] 3'UTB

UGCUGAGCAGAAAACAAAA 1039 UUUUGUUUUCUGCUCAGCA 1654 [3165-3183] 3'UTB

AGCGGUCAGUGAGAAGGAA 1040 UUCCUUCUCACUGACCGCU 1655 [445-463] ORF

GGUAUUAGACUUGCACUUU 1041 AAAGUGCAAGUCUAAUACC 1656 [2913-2931] 3'UTB

GCUGGAAUAUGAAGUCUGA 1042 UCAGACUUCAUAUUCCAGC 1657 Ms [3505-3523] 3'UTB

CCUGUGUUGUAAAGAUAAA 1043 UUUAUCUUUACAACACAGG 1658 Rh [2380-2398] 3'UTB

GGUAAGAUGUCAUAAUGGA 1044 UCCAUUAUGACAUCUUACC 1659 Rh [2694-2712] 3'UTB

GUGGUUUCCUGAAGCCAGU 1045 ACUGGCUUCAGGAAACCAC 1660 [2295-2313] 3'UTB

GGGUCCAAAUUAAUAUGAU 1046 AUCAUAUUAAUUUGGACCC 1661 [1077-1095] 3'UTB

GGAACACACAAGAGUUGUU 1047 AACAACUCUUGUGUGUUCC 1662 [3539-3557] 3'UTB

AGAUUACCUAGCUAAGAAA 1048 UUUCUUAGCUAGGUAAUCU 1663 [2238-2256] 3'UTB

CUGGGAACACACAAGAGUU 1049 AACUCUUGUGUGUUCCCAG 1664 [3536-3554] 3'UTB

UCCCAUGGGUCCAAAUUAA 1050 UUAAUUUGGACCCAUGGGA 1665 [1071-1089] 3'UTB

GUUCUCCAGUUCAAAUUAU 1051 AUAAUUUGAACUGGAGAAC 1666 [3063-3081] 3'UTB

CCAUGGGUCCAAAUUAAUA 1052 UAUUAAUUUGGACCCAUGG 1667 [1073-1091] 3'UTB

UGGGCGUGGUCUUGCAAAA 1053 UUUUGCAAGACCACGCCCA 1668 [2461-2479] 3'UTB

CGUGCUGAGCAGAAAACAA 1054 UUGUUUUCUGCUCAGCACG 1669 [3163-3181] 3'UTB

CGGUCAGUGAGAAGGAAGU 1055 ACUUCCUUCUCACUGACCG 1670 [447-465] ORF

CGAUAUACAGGCACAUUAU 1056 AUAAUGUGCCUGUAUAUCG 1671 [2403-2421] 3'UTB

GCAUUUUGCAGAAACUUUU 1057 AAAAGUUUCUGCAAAAUGC 1672 Rh [1334-1352] 3'UTB

GGACCAGUCCAUGUGAUUU 1058 AAAUCACAUGGACUGGUCC 1673 Rh [2710-2728] 3'UTB

GCUCAAAUACCUUCACAAU 1059 AUUGUGAAGGUAUUUGAGC 1674 [3224-3242] 3'UTB

CACCUUAGCCUGUUCUAUU 1060 AAUAGAACAGGCUAAGGUG 1675 Rh [2492-2510] 3'UTB

GGAUCUCCCAGCUGGGUUA 1061 UAACCCAGCUGGGAGAUCC 1676 [1296-1314] 3'UTB

GUAUUAGACUUGCACUUUU 1062 AAAAGUGCAAGUCUAAUAC 1677 [2914-2932] 3'UTB

AGAGGAUCCAGUAUGAGAU 1063 AUCUCAUACUGGAUCCUCU 1678 Rh,Rb [501-519] ORF

GAACCUAUGUGUUCCCUCA 1064 UGAGGGAACACAUAGGUUC 1679 [2274-2292] 3'UTB

CUGAGUUGCAGAUAUACCA 1065 UGGUAUAUCUGCAACUCAG 1680 Rh [2191-2209] 3'UTB

CUCAAAUACCUUCACAAUA 1066 UAUUGUGAAGGUAUUUGAG 1681 [3225-3243] 3'UTB

UCCUAUUAAUCCUCAGAAU 1067 AUUCUGAGGAUUAAUAGGA 1682 Rh [1571-1589] 3'UTB

CCAGUUCAAAUUAUUGCAA 1068 UUGCAAUAAUUUGAACUGG 1683 [3068-3086] 3'UTB

UGUUUAUGCUGGAAUAUGA 1069 UCAUAUUCCAGCAUAAACA 1684 [3498-3516] 3'UTB

GCACAGAUCUUGAUGACUU 1070 AAGUCAUCAAGAUCUGUGC 1685 Rh [2591-2609] 3'UTB

AACCUGAGUUGCAGAUAUA 1071 UAUAUCUGCAACUCAGGUU 1686 Rh [2188-2206] 3'UTB

CUGCAAGCAACUCAAAAUA 1072 UAUUUUGAGUUGCUUGCAG 1687 [3344-3362] 3'UTB GGCUUUGGUGACACACUCA 1073 UGAGUGUGUCACCAAAGCC 1688 [2086-2104] 3'UTB

GUUGCAAGACUGUGUAGCA 1074 UGCUACACAGUCUUGCAAC 1689 h [1360-1378] 3'UTB

GACAUUUAUGGCAACCCUA 1075 UAGGGUUGCCAUAAAUGUC 1690 [479-497] ORF

GUAUGAGAUCAAGCAGAUA 1076 UAUCUGCUUGAUCUCAUAC 1691 Rh,Rb,Cw,Dg,Rt,Ms [511-529] ORF

GACUUGCUGCCGUAAUUUA 1077 UAAAUUACGGCAGCAAGUC 1692 [3428-3446] 3'UTB

GAAAGAAGGAAUAUCUCAU 1078 AUGAGAUAUUCCUUCUUUC 1693 [618-636] ORF

GAGGAAAGAAGGAAUAUCU 1079 AGAUAUUCCUUCUUUCCUC 1694 Rt [615-633] ORF

CGUGGACAAUAAACAGUAU 1080 AUACUGUUUAUUGUCCACG 1695 [3624-3642] 3'UTB

GGUGAACCUGAGUUGCAGA 1081 UCUGCAACUCAGGUUCACC 1696 Rh [2184-2202] 3'UTB

CCUGCAUCAAGAGAAGUGA 1082 UCACUUCUCUUGAUGCAGG 1697 Rt,Ms [876-894] ORF

AGUCCAUGUGAUUUCAGUA 1083 UACUGAAAUCACAUGGACU 1698 Rh [2715-2733] 3'UTB

AGUAAAGGAUCUUUGAGUA 1084 UACUCAAAGAUCCUUUACU 1699 [3087-3105] 3'UTB

CCCAGAAGAAGAGCCUGAA 1085 UUCAGGCUCUUCUUCUGGG 1700 Rh,Cw,Ms,Pg [717-735] ORF

GACAUCAGCUGUAAUCAUU 1086 AAUGAUUACAGCUGAUGUC 1701 [2864-2882] 3'UTB

CCUCAAAGACUGACAGCCA 1087 UGGCUGUCAGUCUUUGAGG 1702 Rh [1980-1998] 3'UTB

CUCGGUCCGUGGACAAUAA 1088 UUAUUGUCCACGGACCGAG 1703 [3617-3635] 3'UTB

AGGGCAGCCUGGAACCAGU 1089 ACUGGUUCCAGGCUGCCCU 1704 [1525-1543] 3'UTB

CCGUGGACAAUAAACAGUA 1090 UACUGUUUAUUGUCCACGG 1705 [3623-3641] 3'UTB

GAAACGACAUUUAUGGCAA 1091 UUGCCAUAAAUGUCGUUUC 1706 [474-492] ORF

CCUCAGAAUUCCAGUGGGA 1092 UCCCACUGGAAUUCUGAGG 1707 Rh [1581-1599] 3'UTB

GUCACAGAGAAGAACAUCA 1093 UGAUGUUCUUCUCUGUGAC 1708 Rh [833-851] ORF

CCAGUGGCUAGUUCUUGAA 1094 UUCAAGAACUAGCCACUGG 1709 [1539-1557] 3'UTB

GGAACCAGUGGCUAGUUCU 1095 AGAACUAGCCACUGGUUCC 1710 [1535-1553] 3'UTB

UCCAUGUGAUUUCAGUAUA 1096 UAUACUGAAAUCACAUGGA 1711 Rh [2717-2735] 3'UTB

AGGUAUUAGACUUGCACUU 1097 AAGUGCAAGUCUAAUACCU 1712 [2912-2930] 3'UTB

CAUUUGACCCAGAGUGGAA 1098 UUCCACUCUGGGUCAAAUG 1713 [2961-2979] 3'UTB

GCACCUGGAUUGAGUUGCA 1099 UGCAACUCAAUCCAGGUGC 1714 [1847-1865] 3'UTB

AGUUGUUGAAAGUUGACAA 1100 UUGUCAACUUUCAACAACU 1715 [3551-3569] 3'UTB

GUGGCCAACUGC AAAAAAA 1101 UUUUUUUGCAGUUGGCCAC 1716 [984-1002] 3'UTR

CUCAAAGACUGACAGCCAU 1102 AUGGCUGUCAGUCUUUGAG 1717 Rh [1981-1999] 3'UTB

GCCUCAGCUGAGUCUUUUU 1103 AAAAAGACUCAGCUGAGGC 1718 Rh [1658-1676] 3'UTB

UGCUUUGUAUCAUUCUUGA 1104 UCAAGAAUGAUACAAAGCA 1719 [3591-3609] 3'UTB

GUUUAAGAAGGCUCUCCAU 1105 AUGGAGAGCCUUCUUAAAC 1720 [3265-3283] 3'UTB

CCAGCUAAGCAUAGUAAGA 1106 UCUUACUAUGCUUAGCUGG 1721 [2030-2048] 3'UTB

GUUGGUAAGAUGUCAUAAU 1107 AUUAUGACAUCUUACCAAC 1722 Rh [2691-2709] 3'UTB

CACCUGUGUUGUAAAGAUA 1108 UAUCUUUACAACACAGGUG 1723 Rh [2378-2396] 3'UTB

CAGCCUCAGCUGAGUCUUU 1109 AAAGACUCAGCUGAGGCUG 1724 Rh [1656-1674] 3'UTB

AUGAGAUCAAGCAGAUAAA 1110 UUUAUCUGCUUGAUCUCAU 1725 Rh,Cw,Dg,Rt,Ms [513-531] ORF

GUUGCACAGCUUUGCUUUA 1111 UAAAGCAAAGCUGUGCAAC 1726 [1860-1878] 3'UTB

GUGGCUAGUUCUUGAAGGA 1112 UCCUUCAAGAACUAGCCAC 1727 [1542-1560] 3'UTB

GAUUGAGUUGCACAGCUUU 1113 AAAGCUGUGCAACUCAAUC 1728 [1854-1872] 3'UTB

GGAUCUUUGAGUAGGUUCG 1114 CGAACCUACUCAAAGAUCC 1729 [3093-3111] 3'UTB

CGCUGGACGUUGGAGGAAA 1115 UUUCCUCCAACGUCCAGCG 1730 Rt,Ms [603-621] ORF

CACACACGUUGGUCUUUUA 1116 UAAAAGACCAACGUGUGUG 1731 [3142-3160] 3'UTB

CUCAGUGUGGUUUCCUGAA 1117 UUCAGGAAACCACACUGAG 1732 [2289-2307] 3'UTB

AUGUUAUGUUCUAAGCACA 1118 UGUGCUUAGAACAUAACAU 1733 [3303-3321] 3'UTB

GCCACCUUAGCCUGUUCUA 1119 UAGAACAGGCUAAGGUGGC 1734 Rh [2490-2508] 3'UTB AAGAGUUGUUGAAAGUUGA 1120 UCAACUUUCAACAACUCUU 1735 [3548-3566] 3'UTB

CCUGAGAAGGAUAUAGAGU 1121 ACUCUAUAUCCUUCUCAGG 1736 [545-563] ORF

ACCAGUGGCUAGUUCUUGA 1122 UCAAGAACUAGCCACUGGU 1737 [1538-1556] 3'UTB

CAUCCUGCAAGCAACUCAA 1123 UUGAGUUGCUUGCAGGAUG 1738 [3340-3358] 3'UTB

GUAAUGAUAAGGAGAAUCU 1124 AGAUUCUCCUUAUCAUUAC 1739 [2347-2365] 3'UTB

GGAAUAUCUCAUUGCAGGA 1125 UCCUGCAAUGAGAUAUUCC 1740 [625-643] ORF

GGGCGUGGUCUUGCAAAAU 1126 AUUUUGCAAGACCACGCCC 1741 [2462-2480] 3'UTB

CAUCCUGAGGACAGAAAAA 1127 UUUUUCUGUCCUCAGGAUG 1742 h [1921-1939] 3'UTB

UGGACUUGCUGCCGUAAUU 1128 AAUUACGGCAGCAAGUCCA 1743 [3426-3444] 3'UTB

GUGACACACUCACUUCUUU 1129 AAAGAAGUGAGUGUGUCAC 1744 [2093-2111] 3'UTB

CUGUUUUAAGAGACAUCUU 1130 AAGAUGUCUCUUAAAACAG 1745 Rh [2135-2153] 3'UTB

GUUUAUGCUGGAAUAUGAA 1131 UUCAUAUUCCAGCAUAAAC 1746 [3499-3517] 3'UTB

GUCCAUGUGAUUUCAGUAU 1132 AUACUGAAAUCACAUGGAC 1747 Rh [2716-2734] 3'UTB

AGGAGUUUCUCGACAUCGA 1133 UCGAUGUCGAGAAACUCCU 1748 Ck,Dg [936-954] ORF

GAAGAACUUUCUCGGUAAU 1134 AUUACCGAGAAAGUUCUUC 1749 Rh [2333-2351] 3'UTB

GGGUCUGGAGGGAGACGUG 1135 CACGUCUCCCUCCAGACCC 1750 [1130-1148] 3'UTB

GGAAGCCGCUCAAAUACCU 1136 AGGUAUUUGAGCGGCUUCC 1751 [3217-3235] 3'UTB

GGUCCGUGGACAAUAAACA 1137 UGUUUAUUGUCCACGGACC 1752 [3620-3638] 3'UTB

CCCUCCAACCCAUAUAACA 1138 UGUUAUAUGGGUUGGAGGG 1753 [2752-2770] 3'UTB

CCCAUGGGUCCAAAUUAAU 1139 AUUAAUUUGGACCCAUGGG 1754 [1072-1090] 3'UTB

CACACUCACUUCUUUCUCA 1140 UGAGAAAGAAGUGAGUGUG 1755 [2097-2115] 3'UTB

GCAGAAAACAAAACAGGUU 1141 AACCUGUUUUGUUUUCUGC 1756 [3171-3189] 3'UTB

CAUCAAUCCUAUUAAUCCU 1142 AGGAUUAAUAGGAUUGAUG 1757 Rh [1565-1583] 3'UTB

CACAAUAAAUAGUGGCAAU 1143 AUUGCCACUAUUUAUUGUG 1758 [3237-3255] 3'UTB

GUUGGAGGAAAGAAGGAAU 1144 AUUCCUUCUUUCCUCCAAC 1759 Rt [611-629] ORF

GGCCUUUAUAUUUGAUCCA 1145 UGGAUCAAAUAUAAAGGCC 1760 [3125-3143] 3'UTB

UGUUCAAAGGGCCUGAGAA 1146 UUCUCAGGCCCUUUGAACA 1761 [534-552] ORF

ACUGGGUCACAGAGAAGAA 1147 UUCUUCUCUGUGACCCAGU 1762 Rh,Rt,Ms [828-846] ORF

GGUAAUGAUAAGGAGAAUC 1148 GAUUCUCCUUAUCAUUACC 1763 [2346-2364] 3'UTB

CACACAAGAGUUGUUGAAA 1149 UUUCAACAACUCUUGUGUG 1764 [3543-3561] 3'UTB

CUCUGGAUGGACUGGGUCA 1150 UGACCCAGUCCAUCCAGAG 1765 Rh,Rb,Cw,Dg,Rt,Ms, [818-836] ORF

Pg

GGAACUAGGGAACCUAUGU 1151 ACAUAGGUUCCCUAGUUCC 1766 Rh [2265-2283] 3'UTB

CUCGGUAAUGAUAAGGAGA 1152 UCUCCUUAUCAUUACCGAG 1767 [2343-2361] 3'UTB

AGGUGAAUUCUCAGAUGAU 1153 AUCAUCUGAGAAUUCACCU 1768 [2164-2182] 3'UTB

UCGGUAAUGAUAAGGAGAA 1154 UUCUCCUUAUCAUUACCGA 1769 [2344-2362] 3'UTB

GCCAAAGCGGUCAGUGAGA 1155 UCUCACUGACCGCUUUGGC 1770 [440-458] ORF

GAACCAGUGGCUAGUUCUU 1156 AAGAACUAGCCACUGGUUC 1771 [1536-1554] 3'UTB

CCCUUCUCCUUUUAGACAU 1157 AUGUCUAAAAGGAGAAGGG 1772 [1105-1123] 3'UTB

CCACCUUAGCCUGUUCUAU 1158 AUAGAACAGGCUAAGGUGG 1773 Rh [2491-2509] 3'UTB

CCCUGAGCACCACCCAGAA 1159 UUCUGGGUGGUGCUCAGGG 1774 Rh,Pg [705-723] ORF

UGCUGUACAGUGACCUAAA 1160 UUUAGGUCACUGUACAGCA 1775 [2672-2690] 3'UTB

CCUUAGCCUGUUCUAUUCA 1161 UGAAUAGAACAGGCUAAGG 1776 Rh [2494-2512] 3'UTB

GAACUUUCUCGGUAAUGAU 1162 AUCAUUACCGAGAAAGUUC 1777 [2336-2354] 3'UTB

CCUAGGAAGGGAAGGAUUU 1163 AAAUCCUUCCCUUCCUAGG 1778 Rh [2056-2074] 3'UTB

UCAGUGAGAAGGAAGUGGA 1164 UCCACUUCCUUCUCACUGA 1779 [450-468] ORF AUAUGAAGUCUGAGACCUU 1165 AAGGUCUCAGACUUCAUAU 1780 [3511-3529] 3'UTB

GGACUCUGGAAACGACAUU 1166 AAUGUCGUUUCCAGAGUCC 1781 h [466-484] ORF

CCUCUGAGCCUUGUAGAAA 1167 UUUCUACAAGGCUCAGAGG 1782 Rh [1605-1623] 3'UTB

AGUUUAAGAAGGCUCUCCA 1168 UGGAGAGCCUUCUUAAACU 1783 [3264-3282] 3'UTB

AGGGCAGACUGGGAGGGUA 1169 UACCCUCCCAGUCUGCCCU 1784 Rh [2618-2636] 3'UTB

GUAGAAAUGGGAGCGAGAA 1170 UUCUCGCUCCCAUUUCUAC 1785 [1617-1635] 3'UTB

GGACUUGCUGCCGUAAUUU 1171 AAAUUACGGCAGCAAGUCC 1786 [3427-3445] 3'UTB

AGAACUUUCUCGGUAAUGA 1172 UCAUUACCGAGAAAGUUCU 1787 [2335-2353] 3'UTB

GUAUCAUUCUUGAGCAAUC 1173 GAUUGCUCAAGAAUGAUAC 1788 [3597-3615] 3'UTB

CAGCUAAGCAUAGUAAGAA 1174 UUCUUACUAUGCUUAGCUG 1789 [2031-2049] 3'UTB

GGCCUGUUUUAAGAGACAU 1175 AUGUCUCUUAAAACAGGCC 1790 Rh [2132-2150] 3'UTB

GACUGGGUCACAGAGAAGA 1176 UCUUCUCUGUGACCCAGUC 1791 Rh,Rt,Ms [827-845] ORF

CUCUGAUGCUUUGUAUCAU 1177 AUGAUACAAAGCAUCAGAG 1792 [3585-3603] 3'UTB

GUAACAUUUACUCCUGUUU 1178 AAACAGGAGUAAAUGUUAC 1793 Rh [2809-2827] 3'UTB

UGAGUUGCAGAUAUACCAA 1179 UUGGUAUAUCUGCAACUCA 1794 Rh [2192-2210] 3'UTB

AUCCCAUGGGUCCAAAUUA 1180 UAAUUUGGACCCAUGGGAU 1795 [1070-1088] 3'UTB

CUCUGGAAACGACAUUUAU 1181 AUAAAUGUCGUUUCCAGAG 1796 Rh [469-487] ORF

GAUCCAGUAUGAGAUCAAG 1182 CUUGAUCUCAUACUGGAUC 1797 Rh,Rb [505-523] ORF

AGGUGUGGCCUUUAUAUUU 1183 AAAUAUAAAGGCCACACCU 1798 [3119-3137] 3'UTB

CCCUGUUCGCUUCCUGUAU 1184 AUACAGGAAGCGAACAGGG 1799 [2777-2795] 3'UTB

GGGAGACGUGGGUCCAAGG 1185 CCUUGGACCCACGUCUCCC 1800 [1139-1157] 3'UTB

CAUGGGUCCAAAUUAAUAU 1186 AUAUUAAUUUGGACCCAUG 1801 [1074-1092] 3'UTB

UGGGUCACAGAGAAGAACA 1187 UGUUCUUCUCUGUGACCCA 1802 Rh [830-848] ORF

CCUCAAGGUCCCUUCCCUA 1188 UAGGGAAGGGACCUUGAGG 1803 [1786-1804] 3'UTB

UGGUUCUCCAGUUCAAAUU 1189 AAUUUGAACUGGAGAACCA 1804 [3061-3079] 3'UTB

GGACCUGGUCAGCACAGAU 1190 AUCUGUGCUGACCAGGUCC 1805 Rh [2580-2598] 3'UTB

GGAGGGAGACGUGGGUCCA 1191 UGGACCCACGUCUCCCUCC 1806 [1136-1154] 3'UTB

UCUGAUGCUUUGUAUCAUU 1192 AAUGAUACAAAGCAUCAGA 1807 [3586-3604] 3'UTB

GGGACAUGGCCCUUGUUUU 1193 AAAACAAGGGCCAUGUCCC 1808 [1407-1425] 3'UTB

GCCUGGGCGUGGUCUUGCA 1194 UGCAAGACCACGCCCAGGC 1809 [2458-2476] 3'UTB

GGCGUUUUGCAAUGCAGAU 1195 AUCUGCAUUGCAAAACGCC 1810 Cw,Rt,Ms [409-427] ORF

GAGUAGGUUCGGUCUGAAA 1196 UUUCAGACCGAACCUACUC 1811 [3101-3119] 3'UTB

AGUUCUUCGCCUGCAUCAA 1197 UUGAUGCAGGCGAAGAACU 1812 Rh,Rb,Cw,Dg, Ms [867-885] ORF

ACAAAGAUUACCUAGCUAA 1198 UUAGCUAGGUAAUCUUUGU 1813 [2234-2252] 3'UTB

GAGGGAGACGUGGGUCCAA 1199 UUGGACCCACGUCUCCCUC 1814 [1137-1155] 3'UTB

CUGUUUCUGCUGAUUGUUU 1200 AAACAAUCAGCAGAAACAG 1815 [2822-2840] 3'UTB

CUGACGAUAUACAGGCACA 1201 UGUGCCUGUAUAUCGUCAG 1816 [2399-2417] 3'UTB

UGUUGAAAGUUGACAAGCA 1202 UGCUUGUCAACUUUCAACA 1817 [3554-3572] 3'UTB

GCCUAGGAAGGGAAGGAUU 1203 AAUCCUUCCCUUCCUAGGC 1818 Rh [2055-2073] 3'UTB

GGUGACACACUCACUUCUU 1204 AAGAAGUGAGUGUGUCACC 1819 [2092-2110] 3'UTB

GAGCCUUGUAGAAAUGGGA 1205 UCCCAUUUCUACAAGGCUC 1820 Rh [1610-1628] 3'UTB

CAGAAAACAAAACAGGUUA 1206 UAACCUGUUUUGUUUUCUG 1821 [3172-3190] 3'UTB

CGCAUGUCUCUGAUGCUUU 1207 AAAGCAUCAGAGACAUGCG 1822 [3578-3596] 3'UTB

GACAAAGAUUACCUAGCUA 1208 UAGCUAGGUAAUCUUUGUC 1823 [2233-2251] 3'UTB

CUGUAUGGUGAUAUCAUAU 1209 AUAUGAUAUCACCAUACAG 1824 [2790-2808] 3'UTB

GACUCUGGAAACGACAUUU 1210 AAAUGUCGUUUCCAGAGUC 1825 Rh [467-485] ORF GGUUCGGUCUGAAAGGUGU 1211 ACACCUUUCAGACCGAACC 1826 [3106-3124] 3'UTB

AGAUGAUAGGUGAACCUGA 1212 UCAGGUUCACCUAUCAUCU 1827 [2176-2194] 3'UTB

GACACUAUGGCCUGUUUUA 1213 UAAAACAGGCCAUAGUGUC 1828 [2124-2142] 3'UTB

CUGCAAAAAAAGCCUCCAA 1214 UUGGAGGCUUUUUUUGCAG 1829 [992-1010] 3'UTR

CUGUUCUAUUCAGCGGCAA 1215 UUGCCGCUGAAUAGAACAG 1830 [2501-2519] 3'UTB

GUGGGUCCAAGGUCCUCAU 1216 AUGAGGACCUUGGACCCAC 1831 [1146-1164] 3'UTB

GCCUGAGAAGGAUAUAGAG 1217 CUCUAUAUCCUUCUCAGGC 1832 [544-562] ORF

GAAACUUCCUAGGGAACUA 1218 UAGUUCCCUAGGAAGUUUC 1833 [2253-2271] 3'UTB

CGCCAGCUAAGCAUAGUAA 1219 UUACUAUGCUUAGCUGGCG 1834 [2028-2046] 3'UTB

GCCUCUGGAUGGACUGGGU 1220 ACCCAGUCCAUCCAGAGGC 1835 Rh,Rb,Cw,Dg,Rt,Ms [816-834] ORF

ACGAUAUACAGGCACAUUA 1221 UAAUGUGCCUGUAUAUCGU 1836 [2402-2420] 3'UTB

AGCACCACCCAGAAGAAGA 1222 UCUUCUUCUGGGUGGUGCU 1837 Rh,Pg [710-728] ORF

CCUCCCUCAAAGACUGACA 1223 UGUCAGUCUUUGAGGGAGG 1838 Rh [1976-1994] 3'UTB

GGAGCACUGUGUUUAUGCU 1224 AGCAUAAACACAGUGCUCC 1839 [3489-3507] 3'UTB

ACUUGCUGCCGUAAUUUAA 1225 UUAAAUUACGGCAGCAAGU 1840 [3429-3447] 3'UTB

GGUUUCCUGAAGCCAGUGA 1226 UCACUGGCUUCAGGAAACC 1841 [2297-2315] 3'UTB

GGUCAGUGAGAAGGAAGUG 1227 CACUUCCUUCUCACUGACC 1842 [448-466] ORF

GUGACGCCAGCUAAGCAUA 1228 UAUGCUUAGCUGGCGUCAC 1843 [2024-2042] 3'UTB

AUGAUAAGGAGAAUCUCUU 1229 AAGAGAUUCUCCUUAUCAU 1844 [2350-2368] 3'UTB

UAGUGUUCCCUCCCUCAAA 1230 UUUGAGGGAGGGAACACUA 1845 [1968-1986] 3'UTB

GGAGACGUGGGUCCAAGGU 1231 ACCUUGGACCCACGUCUCC 1846 [1140-1158] 3'UTB

CCUGUUCUAUUCAGCGGCA 1232 UGCCGCUGAAUAGAACAGG 1847 [2500-2518] 3'UTB

UCCAGUAUGAGAUCAAGCA 1233 UGCUUGAUCUCAUACUGGA 1848 Rh,Rb [507-525] ORF

CAAAAUGCUUCCAAAGCCA 1234 UGGCUUUGGAAGCAUUUUG 1849 Rh [2475-2493] 3'UTB

CACACGCAAUGAAACCGAA 1235 UUCGGUUUCAUUGCGUGUG 1850 [2431-2449] 3'UTB

CUCCAUUUGGCAUCGUUUA 1236 UAAACGAUGCCAAAUGGAG 1851 [3278-3296] 3'UTB

AGCAGGAGUUUCUCGACAU 1237 AUGUCGAGAAACUCCUGCU 1852 Ck,Dg [933-951] ORF

GUGUGGCCUUUAUAUUUGA 1238 UCAAAUAUAAAGGCCACAC 1853 [3121-3139] 3'UTB

GGGACCUGGUCAGCACAGA 1239 UCUGUGCUGACCAGGUCCC 1854 Rh [2579-2597] 3'UTB

CCUCAGUGUGGUUUCCUGA 1240 UCAGGAAACCACACUGAGG 1855 [2288-2306] 3'UTB

GACCCAGAGUGGAACGCGU 1241 ACGCGUUCCACUCUGGGUC 1856 [2966-2984] 3'UTB

CCACCUGUGUUGUAAAGAU 1242 AUCUUUACAACACAGGUGG 1857 Rh [2377-2395] 3'UTB

ACCUGUGUUGUAAAGAUAA 1243 UUAUCUUUACAACACAGGU 1858 Rh [2379-2397] 3'UTB

GUUUUGCAAUGCAGAUGUA 1244 UACAUCUGCAUUGCAAAAC 1859 [412-430] ORF

AAAAAAGCCUCCAAGGGUU 1245 AACCCUUGGAGGCUUUUUU 1860 [997-1015] 3'UTR

UAAGAAACUUCCUAGGGAA 1246 UUCCCUAGGAAGUUUCUUA 1861 [2250-2268] 3'UTB

GCAUUUGACCCAGAGUGGA 1247 UCCACUCUGGGUCAAAUGC 1862 [2960-2978] 3'UTB

CCCUCAAGGUCCCUUCCCU 1248 AGGGAAGGGACCUUGAGGG 1863 [1785-1803] 3'UTB

AGGAUCCAGUAUGAGAUCA 1249 UGAUCUCAUACUGGAUCCU 1864 Rh,Rb [503-521] ORF

AAGAUUACCUAGCUAAGAA 1250 UUCUUAGCUAGGUAAUCUU 1865 [2237-2255] 3'UTB

CUAUGUGUUCCCUCAGUGU 1251 ACACUGAGGGAACACAUAG 1866 [2278-2296] 3'UTB

GACAGAGGAAGCCGCUCAA 1252 UUGAGCGGCUUCCUCUGUC 1867 [3211-3229] 3'UTB

UUAAGAAGGCUCUCCAUUU 1253 AAAUGGAGAGCCUUCUUAA 1868 [3267-3285] 3'UTB

UAAGGAGAAUCUCUUGUUU 1254 AAACAAGAGAUUCUCCUUA 1869 [2354-2372] 3'UTB

GUUUCCUGAAGCCAGUGAU 1255 AUCACUGGCUUCAGGAAAC 1870 [2298-2316] 3'UTB UGAGCACCACCCAGAAGAA 1256 UUCUUCUGGGUGGUGCUCA 1871 Rh,Pg [708-726] ORF

CUAUUAAUCCUCAGAAUUC 1257 GAAUUCUGAGGAUUAAUAG 1872 h [1573-1591] 3'UTB

CUGGGCGUGGUCUUGCAAA 1258 UUUGCAAGACCACGCCCAG 1873 [2460-2478] 3'UTB

GGAGGAAAGAAGGAAUAUC 1259 GAUAUUCCUUCUUUCCUCC 1874 Rt [614-632] ORF

CCAAGUUCUUCGCCUGCAU 1260 AUGCAGGCGAAGAACUUGG 1875 Rh,Rb,Cw,Dg,Ms [864-882] ORF

GUUUCUGCUGAUUGUUUUU 1261 AAAAACAAUCAGCAGAAAC 1876 [2824-2842] 3'UTB

GGUCCAAGGUCCUCAUCCC 1262 GGGAUGAGGACCUUGGACC 1877 [1149-1167] 3'UTB

AGUUGGUAAGAUGUCAUAA 1263 UUAUGACAUCUUACCAACU 1878 Rh [2690-2708] 3'UTB

GGAAUAUGAAGUCUGAGAC 1264 GUCUCAGACUUCAUAUUCC 1879 Ms [3508-3526] 3'UTB

GAGUGGAACGCGUGGCCUA 1265 UAGGCCACGCGUUCCACUC 1880 [2972-2990] 3'UTB

GGUUGUGGGUCUGGAGGGA 1266 UCCCUCCAGACCCACAACC 1881 Rh [1124-1142] 3'UTB

GUUGAUUUUGUUUCCGUUU 1267 AAACGGAAACAAAAUCAAC 1882 [3454-3472] 3'UTB

CACUGUGUUUAUGCUGGAA 1268 UUCCAGCAUAAACACAGUG 1883 [3493-3511] 3'UTB

GAGCUGCGUUCCAGCCUCA 1269 UGAGGCUGGAACGCAGCUC 1884 [1645-1663] 3'UTB

GGACUGGGUCACAGAGAAG 1270 CUUCUCUGUGACCCAGUCC 1885 Rh,Rt,Ms,Pg [826-844] ORF

AGCUAAGCAUAGUAAGAAG 1271 CUUCUUACUAUGCUUAGCU 1886 [2032-2050] 3'UTB

CACAAGAGUUGUUGAAAGU 1272 ACUUUCAACAACUCUUGUG 1887 [3545-3563] 3'UTB

GGUCAGCACAGAUCUUGAU 1273 AUCAAGAUCUGUGCUGACC 1888 Rh [2586-2604] 3'UTB

UUCUAAAGGUGAAUUCUCA 1274 UGAGAAUUCACCUUUAGAA 1889 [2158-2176] 3'UTB

AGGGAACUAGGGAACCUAU 1275 AUAGGUUCCCUAGUUCCCU 1890 Rh [2263-2281] 3'UTB

GGAAGUGGACUCUGGAAAC 1276 GUUUCCAGAGUCCACUUCC 1891 [460-478] ORF

CCUCCCACCUGUGUUGUAA 1277 UUACAACACAGGUGGGAGG 1892 Rh [2373-2391] 3'UTB

CGGACGAGUGCCUCUGGAU 1278 AUCCAGAGGCACUCGUCCG 1893 Rh,Rb,Cw [807-825] ORF

CGUGGAAGCAUUUGACCCA 1279 UGGGUCAAAUGCUUCCACG 1894 Rh [2953-2971] 3'UTB

GCACUGUGUUUAUGCUGGA 1280 UCCAGCAUAAACACAGUGC 1895 [3492-3510] 3'UTB

AGUUGCAGAUAUACCAACU 1281 AGUUGGUAUAUCUGCAACU 1896 Rh [2194-2212] 3'UTB

AAUGAUAAGGAGAAUCUCU 1282 AGAGAUUCUCCUUAUCAUU 1897 [2349-2367] 3'UTB

CUUGCUGCCGUAAUUUAAA 1283 UUUAAAUUACGGCAGCAAG 1898 [3430-3448] 3'UTB

GGAGAAUCUCUUGUUUCCU 1284 AGGAAACAAGAGAUUCUCC 1899 [2357-2375] 3'UTB

CCUUGGUAGGUAUUAGACU 1285 AGUCUAAUACCUACCAAGG 1900 [2905-2923] 3'UTB

GGACGUUGGAGGAAAGAAG 1286 CUUCUUUCCUCCAACGUCC 1901 Rt,Ms [607-625] ORF

CGUUGGAGGAAAGAAGGAA 1287 UUCCUUCUUUCCUCCAACG 1902 Rt,Ms [610-628] ORF

CUGACAUCCCUUCCUGGAA 1288 UUCCAGGAAGGGAUGUCAG 1903 Rh,Rt,Ms [1031-1049] 3'UTB

UGACAUCCCUUCCUGGAAA 1289 UUUCCAGGAAGGGAUGUCA 1904 Rh,Rt,Ms [1032-1050] 3'UTB

GAUAUACCAACUUCUGCUU 1290 AAGCAGAAGUUGGUAUAUC 1905 Rh [2201-2219] 3'UTB

AGAUGGGCUGCGAGUGCAA 1291 UUGCACUCGCAGCCCAUCU 1906 Ck,Rb,Rt [747-765] ORF

GGCUUAGUGUUCCCUCCCU 1292 AGGGAGGGAACACUAAGCC 1907 [1964-1982] 3'UTB

GUAUGGUGAUAUCAUAUGU 1293 ACAUAUGAUAUCACCAUAC 1908 [2792-2810] 3'UTB

ACCAACUUCUGCUUGUAUU 1294 AAUACAAGCAGAAGUUGGU 1909 Rh [2206-2224] 3'UTB

CUCACUUCUUUCUCAGCCU 1295 AGGCUGAGAAAGAAGUGAG 1910 [2101-2119] 3'UTB

CUCCCACCUGUGUUGUAAA 1296 UUUACAACACAGGUGGGAG 1911 Rh [2374-2392] 3'UTB

GGGUCUCGCUGGACGUUGG 1297 CCAACGUCCAGCGAGACCC 1912 Rt,Ms [597-615] ORF

GAGCCUCCCUCUGAGCCUU 1298 AAGGCUCAGAGGGAGGCUC 1913 Rh [1598-1616] 3'UTB

GCAUGUCUCUGAUGCUUUG 1299 CAAAGCAUCAGAGACAUGC 1914 [3579-3597] 3'UTB

GGCGUUUUCAUGCUGUACA 1300 UGUACAGCAUGAAAACGCC 1915 Rh [2662-2680] 3'UTB

AUACCAACUUCUGCUUGUA 1301 UACAAGCAGAAGUUGGUAU 1916 Rh [2204-2222] 3'UTB

GCAAUGCAGAUGUAGUGAU 1302 AUCACUACAUCUGCAUUGC 1917 [417-435] ORF

ACUUCUGCUUGUAUUUCUU 1303 AAGAAAUACAAGCAGAAGU 1918 Rh [2210-2228] 3'UTB UCCAGUUCAAAUUAUUGCA 1304 UGCAAUAAUUUGAACUGGA 1919 [3067-3085] 3'UTB

CCUGGUCAGCACAGAUCUU 1305 AAGAUCUGUGCUGACCAGG 1920 h [2583-2601] 3'UTB

UGUUGAUUUUGUUUCCGUU 1306 AACGGAAACAAAAUCAACA 1921 [3453-3471] 3'UTB

UGCAGAUAUACCAACUUCU 1307 AGAAGUUGGUAUAUCUGCA 1922 Rh [2197-2215] 3'UTR

GCGGUCAGUGAGAAGGAAG 1308 CUUCCUUCUCACUGACCGC 1923 [446-464] ORF

GGCGUGGUCUUGCAAAAUG 1309 CAUUUUGCAAGACCACGCC 1924 [2463-2481] 3'UTB

GUCCAGCCUAGGAAGGGAA 1310 UUCCCUUCCUAGGCUGGAC 1925 Rh [2050-2068] 3'UTR

ACUUUCUCGGUAAUGAUAA 1311 UUAUCAUUACCGAGAAAGU 1926 [2338-2356] 3'UTB

CUUCUGCUUGUAUUUCUUA 1312 UAAGAAAUACAAGCAGAAG 1927 [2211-2229] 3'UTB

CAGAGGAAGCCGCUCAAAU 1313 AUUUGAGCGGCUUCCUCUG 1928 [3213-3231] 3'UTB

GAAGGAAGUGGACUCUGGA 1314 UCCAGAGUCCACUUCCUUC 1929 [457-475] ORF

CAGUGAGAAGGAAGUGGAC 1315 GUCCACUUCCUUCUCACUG 1930 [451-469] ORF

GACUUCCCUUUCUAGGGCA 1316 UGCCCUAGAAAGGGAAGUC 1931 Rh [2605-2623] 3'UTB

CCUCCCUCUGAGCCUUGUA 1317 UACAAGGCUCAGAGGGAGG 1932 Rh [1601-1619] 3'UTB

CAUGCUGUACAGUGACCUA 1318 UAGGUCACUGUACAGCAUG 1933 [2670-2688] 3'UTB

GAGUGCCUCUGGAUGGACU 1319 AGUCCAUCCAGAGGCACUC 1934 Rh,Rb,Cw,Dg,Rt,Ms [812-830] ORF

CUGGGAGGGUAUCCAGGAA 1320 UUCCUGGAUACCCUCCCAG 1935 Rh [2626-2644] 3'UTB

AACCGUGCUGAGCAGAAAA 1321 UUUUCUGCUCAGCACGGUU 1936 [3160-3178] 3'UTB

CAGUCCAUGUGAUUUCAGU 1322 ACUGAAAUCACAUGGACUG 1937 Rh [2714-2732] 3'UTB

UAGACAUGGUUGUGGGUCU 1323 AGACCCACAACCAUGUCUA 1938 [1117-1135] 3'UTB

GCGCAUGUCUCUGAUGCUU 1324 AAGCAUCAGAGACAUGCGC 1939 [3577-3595] 3'UTB

AAGGUGAAUUCUCAGAUGA 1325 UCAUCUGAGAAUUCACCUU 1940 [2163-2181] 3'UTB

AGAAGAACAUCAACGGGCA 1326 UGCCCGUUGAUGUUCUUCU 1941 Rh,Rb [840-858] ORF

ACAUACACACGCAAUGAAA 1327 UUUCAUUGCGUGUGUAUGU 1942 Rh [2426-2444] 3'UTB

CACAGAUCUUGAUGACUUC 1328 GAAGUCAUCAAGAUCUGUG 1943 Rh [2592-2610] 3'UTB

AGCCGCUCAAAUACCUUCA 1329 UGAAGGUAUUUGAGCGGCU 1944 [3220-3238] 3'UTB

CCAGUAUGAGAUCAAGCAG 1330 CUGCUUGAUCUCAUACUGG 1945 Rh,Rb,Cw,Dg,Ms [508-526] ORF

GUGAGAAGGAAGUGGACUC 1331 GAGUCCACUUCCUUCUCAC 1946 [453-471] ORF

ACCUUAGCCUGUUCUAUUC 1332 GAAUAGAACAGGCUAAGGU 1947 Rh [2493-2511] 3'UTB

CCUGUUUCUGCUGAUUGUU 1333 AACAAUCAGCAGAAACAGG 1948 [2821-2839] 3'UTB

GCCAUUGCUUCUUGCCUGU 1334 ACAGGCAAGAAGCAAUGGC 1949 [1817-1835] 3'UTB

GCCUGGAAAUGUGCAUUUU 1335 AAAAUGCACAUUUCCAGGC 1950 Rh [1322-1340] 3'UTB

GCACAGCUCUCUUCUCCUA 1336 UAGGAGAAGAGAGCUGUGC 1951 [3317-3335] 3'UTB

CGACAUUUAUGGCAACCCU 1337 AGGGUUGCCAUAAAUGUCG 1952 [478-496] ORF

CCUGUGCUGUGUUUUUUAU 1338 AUAAAAAACACAGCACAGG 1953 Rh [2883-2901] 3'UTB

AGGAAGUGGACUCUGGAAA 1339 UUUCCAGAGUCCACUUCCU 1954 [459-477] ORF

GCUAAGCAUAGUAAGAAGU 1340 ACUUCUUACUAUGCUUAGC 1955 [2033-2051] 3'UTB

CCGUCUUUGGUUCUCCAGU 1341 ACUGGAGAACCAAAGACGG 1956 [3054-3072] 3'UTB

UUUCCUGAAGCCAGUGAUA 1342 UAUCACUGGCUUCAGGAAA 1957 [2299-2317] 3'UTB

AGACGUGGGUCCAAGGUCC 1343 GGACCUUGGACCCACGUCU 1958 [1142-1160] 3'UTB

ACAUUUAUGGCAACCCUAU 1344 AUAGGGUUGCCAUAAAUGU 1959 [480-498] ORF

GUGGACAAUAAACAGUAUU 1345 AAUACUGUUUAUUGUCCAC 1960 [3625-3643] 3'UTB

GGGAACACACAAGAGUUGU 1346 ACAACUCUUGUGUGUUCCC 1961 [3538-3556] 3'UTB

GCUCGGUCCGUGGACAAUA 1347 UAUUGUCCACGGACCGAGC 1962 [3616-3634] 3'UTB

CCGUGCUGAGCAGAAAACA 1348 UGUUUUCUGCUCAGCACGG 1963 [3162-3180] 3'UTB

CCGCUCAAAUACCUUCACA 1349 UGUGAAGGUAUUUGAGCGG 1964 [3222-3240] 3'UTB GUUCCCUCCCUCAAAGACU 1350 AGUCUUUGAGGGAGGGAAC 1965 [1972-1990] 3'UTB

GGUCGUUGCAAGACUGUGU 1351 ACACAGUCUUGCAACGACC 1966 [1356-1374] 3'UTB

GGUGCUGGGAACACACAAG 1352 CUUGUGUGUUCCCAGCACC 1967 [3532-3550] 3'UTB

AGUAUAUACAACUCCACCA 1353 UGGUGGAGUUGUAUAUACU 1968 h [2730-2748] 3'UTB

GGCAUCAGGCACCUGGAUU 1354 AAUCCAGGUGCCUGAUGCC 1969 [1839-1857] 3'UTB

AGCAGAUAAAGAUGUUCAA 1355 UUGAACAUCUUUAUCUGCU 1970 Cw,Dg,Rt,Ms,Pg [522-540] ORF

UGGAAUAUGAAGUCUGAGA 1356 UCUCAGACUUCAUAUUCCA 1971 Ms [3507-3525] 3'UTB

CAGGCACCUGGAUUGAGUU 1357 AACUCAAUCCAGGUGCCUG 1972 Rh [1844-1862] 3'UTB

AUAAGGAGAAUCUCUUGUU 1358 AACAAGAGAUUCUCCUUAU 1973 [2353-2371] 3'UTB

GCCUGUUUUAAGAGACAUC 1359 GAUGUCUCUUAAAACAGGC 1974 Rh [2133-2151] 3'UTB

CGCUUCCUGUAUGGUGAUA 1360 UAUCACCAUACAGGAAGCG 1975 [2784-2802] 3'UTB

GCACCGUCACAGAUGCCAA 1361 UUGGCAUCUGUGACGGUGC 1976 [1262-1280] 3'UTB

GUUCCAGCCUCAGCUGAGU 1362 ACUCAGCUGAGGCUGGAAC 1977 [1652-1670] 3'UTB

GGAGGUAGGUGGCUUUGGU 1363 ACCAAAGCCACCUACCUCC 1978 Rh [2076-2094] 3'UTB

GGAAACGACAUUUAUGGCA 1364 UGCCAUAAAUGUCGUUUCC 1979 [473-491] ORF

GCAAGAUGCACAUCACCCU 1365 AGGGUGAUGUGCAUCUUGC 1980 Rh,Dg [660-678] ORF

UGUAGAAAUGGGAGCGAGA 1366 UCUCGCUCCCAUUUCUACA 1981 Rh [1616-1634] 3TJTB

GGCCUAUGCAGGUGGAUUC 1367 GAAUCCACCUGCAUAGGCC 1982 Rh [2985-3003] 3'UTB

AAGAAGAGCCUGAACCACA 1368 UGUGGUUCAGGCUCUUCUU 1983 Rh,Rb,Cw,Ms,Pg [722-740] ORF

GGGAGGGUAUCCAGGAAUC 1369 GAUUCCUGGAUACCCUCCC 1984 Rh [2628-2646] 3'UTB

GUCAUAAUGGACCAGUCCA 1370 UGGACUGGUCCAUUAUGAC 1985 Rh [2702-2720] 3'UTB

CCAAGGUCCUCAUCCCAUC 1371 GAUGGGAUGAGGACCUUGG 1986 [1152-1170] 3'UTB

AGGUGGCUUUGGUGACACA 1372 UGUGUCACCAAAGCCACCU 1987 Rh [2082-2100] 3'UTB

AGACUGUGUAGCAGGCCUA 1373 UAGGCCUGCUACACAGUCU 1988 Rh [1366-1384] 3'UTB

GGCCUGGAAAUGUGCAUUU 1374 AAAUGCACAUUUCCAGGCC 1989 Rh [1321-1339] 3'UTB

GGUUAGGAUAGGAAGAACU 1375 AGUUCUUCCUAUCCUAACC 1990 [2322-2340] 3'UTB

GGCUAGUUCUUGAAGGAGC 1376 GCUCCUUCAAGAACUAGCC 1991 [1544-1562] 3'UTB

AGCUCUGUUGAUUUUGUUU 1377 AAACAAAAUCAACAGAGCU 1992 [3448-3466] 3'UTB

UGCAUUUUGCAGAAACUUU 1378 AAAGUUUCUGCAAAAUGCA 1993 Rh [1333-1351] 3'UTB

GUCUGAAAGGUGUGGCCUU 1379 AAGGCCACACCUUUCAGAC 1994 [3112-3130] 3'UTB

CAUCCAAGGGCAGCCUGGA 1380 UCCAGGCUGCCCUUGGAUG 1995 [1519-1537] 3'UTB

UGUUUCUGCUGAUUGUUUU 1381 AAAACAAUCAGCAGAAACA 1996 [2823-2841] 3'UTB

UGCAAGCAACUCAAAAUAU 1382 AUAUUUUGAGUUGCUUGCA 1997 [3345-3363] 3'UTB

AACAUUUACUCCUGUUUCU 1383 AGAAACAGGAGUAAAUGUU 1998 Rh [2811-2829] 3'UTB

GAAAGGUGUGGCCUUUAUA 1384 UAUAAAGGCCACACCUUUC 1999 [3116-3134] 3'UTB

UCCUGUUUCUGCUGAUUGU 1385 ACAAUCAGCAGAAACAGGA 2000 [2820-2838] 3'UTB

AUCCUAUUAAUCCUCAGAA 1386 UUCUGAGGAUUAAUAGGAU 2001 Rh [1570-1588] 3'UTB

UCCUGAAGCCAGUGAUAUG 1387 CAUAUCACUGGCUUCAGGA 2002 [2301-2319] 3'UTB

AGGGCCUGAGAAGGAUAUA 1388 UAUAUCCUUCUCAGGCCCU 2003 [541-559] ORF

GUUGCAGAUAUACCAACUU 1389 AAGUUGGUAUAUCUGCAAC 2004 Rh [2195-2213] 3'UTB

GGGCCUGAGAAGGAUAUAG 1390 CUAUAUCCUUCUCAGGCCC 2005 [542-560] ORF

CGGGCGUUUUCAUGCUGUA 1391 UACAGCAUGAAAACGCCCG 2006 Rh [2660-2678] 3'UTB

ACCAGUCCAUGUGAUUUCA 1392 UGAAAUCACAUGGACUGGU 2007 Rh [2712-2730] 3'UTB

CGUGGGUCCAAGGUCCUCA 1393 UGAGGACCUUGGACCCACG 2008 [1145-1163] 3'UTB

GCCUGGAACCAGUGGCUAG 1394 CUAGCCACUGGUUCCAGGC 2009 [1531-1549] 3'UTB

CCUUUCAUCUUGAGAGGGA 1395 UCCCUCUCAAGAUGAAAGG 2010 Rh [1392-1410] 3'UTB

CCAGUGGGAGCCUCCCUCU 1396 AGAGGGAGGCUCCCACUGG 2011 Rh [1591-1609] 3'UTB AAAUGUGCAUUUUGCAGAA 1397 UUCUGCAAAAUGCACAUUU 2012 R ,Ms [1328-1346] 3'UTB

UGGUCAGCACAGAUCUUGA 1398 UCAAGAUCUGUGCUGACCA 2013 h [2585-2603] 3'UTB

CUAUGCAGGUGGAUUCCUU 1399 AAGGAAUCCACCUGCAUAG 2014 R [2988-3006] 3'UTR

AGUAAGAAGUCCAGCCUAG 1400 CUAGGCUGGACUUCUUACU 2015 Rh [2042-2060] 3'UTB

CUCAUCCCAUGGGUCCAAA 1401 UUUGGACCCAUGGGAUGAG 2016 [1067-1085] 3'UTB

AGAGCCGGGUGGCAGCUGA 1402 UCAGCUGCCACCCGGCUCU 2017 [3194-3212] 3'UTB

GCUGGGAACACACAAGAGU 1403 ACUCUUGUGUGUUCCCAGC 2018 [3535-3553] 3'UTB

CCGGACGAGUGCCUCUGGA 1404 UCCAGAGGCACUCGUCCGG 2019 Rh,Rb,Cw [806-824] ORF

CCCUCAGUGUGGUUUCCUG 1405 CAGGAAACCACACUGAGGG 2020 [2287-2305] 3'UTB

AGUUGCACAGCUUUGCUUU 1406 AAAGCAAAGCUGUGCAACU 2021 [1859-1877] 3'UTB

CCCAUAAGCAGGCCUCCAA 1407 UUGGAGGCCUGCUUAUGGG 2022 [958-976]

ORF+3'UTR

CGGUGCUGGGAACACACAA 1408 UUGUGUGUUCCCAGCACCG 2023 [3531-3549] 3'UTB

GGUUUGUUUUUGACAUCAG 1409 CUGAUGUCAAAAACAAACC 2024 Rh [2853-2871] 3'UTB

GACGAUAUACAGGCACAUU 1410 AAUGUGCCUGUAUAUCGUC 2025 [2401-2419] 3'UTB

CUUAGUGUUCCCUCCCUCA 1411 UGAGGGAGGGAACACUAAG 2026 [1966-1984] 3'UTB

GACACACUCACUUCUUUCU 1412 AGAAAGAAGUGAGUGUGUC 2027 [2095-2113] 3'UTB

GAAGCCGCUCAAAUACCUU 1413 AAGGUAUUUGAGCGGCUUC 2028 [3218-3236] 3'UTB

GGUCCCUUUCAUCUUGAGA 1414 UCUCAAGAUGAAAGGGACC 2029 Rh [1388-1406] 3'UTB

CCUGGAACCAGUGGCUAGU 1415 ACUAGCCACUGGUUCCAGG 2030 [1532-1550] 3'UTB

UUCAGUAUAUACAACUCCA 1416 UGGAGUUGUAUAUACUGAA 2031 Rh [2727-2745] 3'UTB

ACCUAUGUGUUCCCUCAGU 1417 ACUGAGGGAACACAUAGGU 2032 [2276-2294] 3'UTB

CUCCUAUUUUCAUCCUGCA 1418 UGCAGGAUGAAAAUAGGAG 2033 [3330-3348] 3'UTB

ACACACAAGAGUUGUUGAA 1419 UUCAACAACUCUUGUGUGU 2034 [3542-3560] 3'UTB

UGUCUCUGAUGCUUUGUAU 1420 AUACAAAGCAUCAGAGACA 2035 [3582-3600] 3'UTB

UAGAAAUGGGAGCGAGAAA 1421 UUUCUCGCUCCCAUUUCUA 2036 [1618-1636] 3'UTB

GAAGCAUUUGACCCAGAGU 1422 ACUCUGGGUCAAAUGCUUC 2037 [2957-2975] 3'UTB

GUUUUUGACAUCAGCUGUA 1423 UACAGCUGAUGUCAAAAAC 2038 [2858-2876] 3'UTB

GGAGUUUCUCGACAUCGAG 1424 CUCGAUGUCGAGAAACUCC 2039 Ck,Dg [937-955] ORF

GAUAAACUGACGAUAUACA 1425 UGUAUAUCGUCAGUUUAUC 2040 [2393-2411] 3'UTB

GUGUUCCCUCCCUCAAAGA 1426 UCUUUGAGGGAGGGAACAC 2041 [1970-1988] 3'UTB

UUUGUUUCCGUUUGGAUUU 1427 AAAUCCAAACGGAAACAAA 2042 [3460-3478] 3'UTB

AGCUGAGUCUUUUUGGUCU 1428 AGACCAAAAAGACUCAGCU 2043 Rh [1663-1681] 3'UTB

AACUUUCUCGGUAAUGAUA 1429 UAUCAUUACCGAGAAAGUU 2044 [2337-2355] 3'UTB

CCGGGUGGCAGCUGACAGA 1430 UCUGUCAGCUGCCACCCGG 2045 [3198-3216] 3'UTB

GAGUUGCACAGCUUUGCUU 1431 AAGCAAAGCUGUGCAACUC 2046 [1858-1876] 3'UTB

CCGGGACCUGGUCAGCACA 1432 UGUGCUGACCAGGUCCCGG 2047 Rh [2577-2595] 3'UTB

CAAAGUAAAGGAUCUUUGA 1433 UCAAAGAUCCUUUACUUUG 2048 [3084-3102] 3'UTB

CAGCUCUCUUCUCCUAUUU 1434 AAAUAGGAGAAGAGAGCUG 2049 [3320-3338] 3'UTB

GACAGAAAAAGCUGGGUCU 1435 AGACCCAGCUUUUUCUGUC 2050 Rh [1930-1948] 3'UTB

UGCAUGUGACGCCAGCUAA 1436 UUAGCUGGCGUCACAUGCA 2051 [2019-2037] 3'UTB

CCAGCCUCAGCUGAGUCUU 1437 AAGACUCAGCUGAGGCUGG 2052 Rh [1655-1673] 3TJTB

GACCUAAAGUUGGUAAGAU 1438 AUCUUACCAACUUUAGGUC 2053 [2683-2701] 3'UTB

GGUGUGGCCUUUAUAUUUG 1439 CAAAUAUAAAGGCCACACC 2054 [3120-3138] 3'UTB

GUCCAAGGUCCUCAUCCCA 1440 UGGGAUGAGGACCUUGGAC 2055 [1150-1168] 3'UTB

UAGUAAGAAGUCCAGCCUA 1441 UAGGCUGGACUUCUUACUA 2056 Rh [2041-2059] 3'UTB AAGCAUAGUAAGAAGUCCA 1442 UGGACUUCUUACUAUGCUU 2057 [2036-2054] 3'UTB

AGGAUAGGAAGAACUUUCU 1443 AGAAAGUUCUUCCUAUCCU 2058 [2326-2344] 3'UTB

AGGAGAAUCUCUUGUUUCC 1444 GGAAACAAGAGAUUCUCCU 2059 [2356-2374] 3'UTB

CAAGAGUUGUUGAAAGUUG 1445 CAACUUUCAACAACUCUUG 2060 [3547-3565] 3'UTB

CCCAUGAUCCCGUGCUACA 1446 UGUAGCACGGGAUCAUGGG 2061 h, b [779-797] ORF

CAUCCCAUGGGUCCAAAUU 1447 AAUUUGGACCCAUGGGAUG 2062 [1069-1087] 3'UTB

CUGAGCAGAAAACAAAACA 1448 UGUUUUGUUUUCUGCUCAG 2063 [3167-3185] 3'UTB

AGCAGAAAACAAAACAGGU 1449 ACCUGUUUUGUUUUCUGCU 2064 [3170-3188] 3'UTB

CUUGUUUCCUCCCACCUGU 1450 ACAGGUGGGAGGAAACAAG 2065 [2366-2384] 3'UTB

GUGGACUCUGGAAACGACA 1451 UGUCGUUUCCAGAGUCCAC 2066 Rh [464-482] ORF

UGAUAAGGAGAAUCUCUUG 1452 CAAGAGAUUCUCCUUAUCA 2067 Rh [2351-2369] 3'UTB

UGAGUAGGUUCGGUCUGAA 1453 UUCAGACCGAACCUACUCA 2068 [3100-3118] 3'UTB

CAUUUGGCAUCGUUUAAUU 1454 AAUUAAACGAUGCCAAAUG 2069 [3281-3299] 3'UTB

GCUUCCUGUAUGGUGAUAU 1455 AUAUCACCAUACAGGAAGC 2070 [2785-2803] 3'UTB

GAGGAUCCAGUAUGAGAUC 1456 GAUCUCAUACUGGAUCCUC 2071 Rh,Rb [502-520] ORF

GCACAUCCUGAGGACAGAA 1457 UUCUGUCCUCAGGAUGUGC 2072 Rh [1918-1936] 3'UTB

GCAUGAAUAAAACACUCAU 1458 AUGAGUGUUUUAUUCAUGC 2073 Rh [1053-1071] 3'UTB

GCAACAGGCGUUUUGCAAU 1459 AUUGCAAAACGCCUGUUGC 2074 Cw,Rt,Ms [403-421] ORF

GGGACGGCAAGAUGCACAU 1460 AUGUGCAUCUUGCCGUCCC 2075 [654-672] ORF

CUGUAAUCAUUCCUGUGCU 1461 AGCACAGGAAUGAUUACAG 2076 Rh [2872-2890] 3'UTB

GGUCUUUUAACCGUGCUGA 1462 UCAGCACGGUUAAAAGACC 2077 [3152-3170] 3'UTB

ACAGCUCUCUUCUCCUAUU 1463 AAUAGGAGAAGAGAGCUGU 2078 [3319-3337] 3'UTB

ACCCUUGGUAGGUAUUAGA 1464 UCUAAUACCUACCAAGGGU 2079 [2903-2921] 3'UTB

GACUGGUCCAGCUCUGACA 1465 UGUCAGAGCUGGACCAGUC 2080 Rh [1018-1036] 3'UTB

AUCCUGCAAGCAACUCAAA 1466 UUUGAGUUGCUUGCAGGAU 2081 [3341-3359] 3'UTB

CCAUGAUCCCGUGCUACAU 1467 AUGUAGCACGGGAUCAUGG 2082 Rh,Rb [780-798] ORF

UUGUAUCAUUCUUGAGCAA 1468 UUGCUCAAGAAUGAUACAA 2083 [3595-3613] 3'UTB

GAGUCUUUUUGGUCUGCAC 1469 GUGCAGACCAAAAAGACUC 2084 [1667-1685] 3'UTB

GUUCAAAGGGCCUGAGAAG 1470 CUUCUCAGGCCCUUUGAAC 2085 [535-553] ORF

AGCCUCAGCUGAGUCUUUU 1471 AAAAGACUCAGCUGAGGCU 2086 Rh [1657-1675] 3'UTB

GAUAAGGAGAAUCUCUUGU 1472 ACAAGAGAUUCUCCUUAUC 2087 [2352-2370] 3'UTB

ACAUCACCCUCUGUGACUU 1473 AAGUCACAGAGGGUGAUGU 2088 Rh [669-687] ORF

GCGUGGUCUUGCAAAAUGC 1474 GCAUUUUGCAAGACCACGC 2089 [2464-2482] 3'UTB

GCCUUGGCACCGUCACAGA 1475 UCUGUGACGGUGCCAAGGC 2090 Rh [1256-1274] 3'UTB

AGAAGAGCCUGAACCACAG 1476 CUGUGGUUCAGGCUCUUCU 2091 Rh,Rb,Cw,Ms, Pg [723-741] ORF

UGGCCUGUUUUAAGAGACA 1477 UGUCUCUUAAAACAGGCCA 2092 Rh [2131-2149] 3'UTB

GGGAAGGAUUUUGGAGGUA 1478 UACCUCCAAAAUCCUUCCC 2093 Rh [2064-2082] 3'UTB

CCCUGUGGCCAACUGCAAA 1479 UUUGCAGUUGGCCACAGGG 2094 Rh [980-998] 3'UTR

CUUUCUCGGUAAUGAUAAG 1480 CUUAUCAUUACCGAGAAAG 2095 [2339-2357] 3'UTB

CACUCAUCCCAUGGGUCCA 1481 UGGACCCAUGGGAUGAGUG 2096 [1065-1083] 3'UTB

GGUGGCAGCUGACAGAGGA 1482 UCCUCUGUCAGCUGCCACC 2097 [3201-3219] 3'UTB

GUGAAUUCUCAGAUGAUAG 1483 CUAUCAUCUGAGAAUUCAC 2098 [2166-2184] 3'UTB

UCCUGCAAGCAACUCAAAA 1484 UUUUGAGUUGCUUGCAGGA 2099 [3342-3360] 3'UTB

CCUGUUUUAAGAGACAUCU 1485 AGAUGUCUCUUAAAACAGG 2100 Rh [2134-2152] 3'UTB

GGGCAGCCUGGAACCAGUG 1486 CACUGGUUCCAGGCUGCCC 2101 [1526-1544] 3'UTB

GCAUCAGGCACCUGGAUUG 1487 CAAUCCAGGUGCCUGAUGC 2102 [1840-1858] 3'UTB AGCCUGGAACCAGUGGCUA 1488 UAGCCACUGGUUCCAGGCU 2103 [1530-1548] 3'UTB

UGCACAUCACCCUCUGUGA 1489 UCACAGAGGGUGAUGUGCA 2104 h [666-684] ORF

AGAUAUACCAACUUCUGCU 1490 AGCAGAAGUUGGUAUAUCU 2105 Rh [2200-2218] 3'UTR

CUAGCUAAGAAACUUCCUA 1491 UAGGAAGUUUCUUAGCUAG 2106 [2245-2263] 3'UTB

CUCUCUUCUCCUAUUUUCA 1492 UGAAAAUAGGAGAAGAGAG 2107 [3323-3341] 3'UTB

AUCCAAGGGCAGCCUGGAA 1493 UUCCAGGCUGCCCUUGGAU 2108 [1520-1538] 3'UTB

AAAGGAUCUUUGAGUAGGU 1494 ACCUACUCAAAGAUCCUUU 2109 [3090-3108] 3'UTB

CUGAGCACCACCCAGAAGA 1495 UCUUCUGGGUGGUGCUCAG 2110 Rh,Pg [707-725] ORF

CCUGUUCUGGCAUCAGGCA 1496 UGCCUGAUGCCAGAACAGG 2111 [1831-1849] 3'UTB

UGUGUUUAUGCUGGAAUAU 1497 AUAUUCCAGCAUAAACACA 2112 [3496-3514] 3'UTB

AGGAAGAACUUUCUCGGUA 1498 UACCGAGAAAGUUCUUCCU 2113 Rh [2331-2349] 3'UTB

AGAGCCUGAACCACAGGUA 1499 UACCUGUGGUUCAGGCUCU 2114 Rh,Rb,Cw,Ms, Pg [726-744] ORF

GCCAAGCAGGCAGCACUUA 1500 UAAGUGCUGCCUGCUUGGC 2115 [1276-1294] 3'UTB

GGGCUUUCUGCAUGUGACG 1501 CGUCACAUGCAGAAAGCCC 2116 [2011-2029] 3'UTB

ACCCAGAAGAAGAGCCUGA 1502 UCAGGCUCUUCUUCUGGGU 2117 Rh,Cw,Ms,Pg [716-734] ORF

CGCCUGCAUCAAGAGAAGU 1503 ACUUCUCUUGAUGCAGGCG 2118 Rh,Cw,Dg,Rt,Ms [874-892] ORF

GCAGAUAUACCAACUUCUG 1504 CAGAAGUUGGUAUAUCUGC 2119 Rh [2198-2216] 3'UTB

UGGACCAGUCCAUGUGAUU 1505 AAUCACAUGGACUGGUCCA 2120 Rh [2709-2727] 3'UTB

UGUAACAUUUACUCCUGUU 1506 AACAGGAGUAAAUGUUACA 2121 Rh [2808-2826] 3'UTB

CAGCUGUAAUCAUUCCUGU 1507 ACAGGAAUGAUUACAGCUG 2122 [2869-2887] 3'UTB

GAGUUGUUGAAAGUUGACA 1508 UGUCAACUUUCAACAACUC 2123 [3550-3568] 3'UTB

AGACUGCGCAUGUCUCUGA 1509 UCAGAGACAUGCGCAGUCU 2124 [3572-3590] 3'UTB

UCCUGUGCUGUGUUUUUUA 1510 UAAAAAACACAGCACAGGA 2125 Rh [2882-2900] 3'UTB

CCUUCUCCUUUUAGACAUG 1511 CAUGUCUAAAAGGAGAAGG 2126 [1106-1124] 3'UTB

CUAAGAAACUUCCUAGGGA 1512 UCCCUAGGAAGUUUCUUAG 2127 [2249-2267] 3'UTB

GCCAAGUUCUUCGCCUGCA 1513 UGCAGGCGAAGAACUUGGC 2128 Rh,Rb,Cw,Dg, Ms [863-881] ORF

GCUGGACGUUGGAGGAAAG 1514 CUUUCCUCCAACGUCCAGC 2129 Rt,Ms [604-622] ORF

AGGCGUUUUGCAAUGCAGA 1515 UCUGCAUUGCAAAACGCCU 2130 Cw,Rt,Ms [408-426] ORF

UGUGCAUUUUGCAGAAACU 1516 AGUUUCUGCAAAAUGCACA 2131 Rh,Rt,Ms [1331-1349] 3'UTB

CAGCCUGGAACCAGUGGCU 1517 AGCCACUGGUUCCAGGCUG 2132 [1529-1547] 3'UTB

GCAAAAAAAGCCUCCAAGG 1518 CCUUGGAGGCUUUUUUUGC 2133 [994-1012] 3'UTR

ACCUGGAUUGAGUUGCACA 1519 UGUGCAACUCAAUCCAGGU 2134 [1849-1867] 3'UTB

CGUAAUUUAAAGCUCUGUU 1520 AACAGAGCUUUAAAUUACG 2135 [3438-3456] 3'UTB

CUGUGCUGUGUUUUUUAUU 1521 AAUAAAAAACACAGCACAG 2136 Rh [2884-2902] 3'UTB

GGCACCAGGCCAAGUUCUU 1522 AAGAACUUGGCCUGGUGCC 2137 Rh,Rb,Rt,Ms [855-873] ORF

CCUGUGGCCAACUGCAAAA 1523 UUUUGCAGUUGGCCACAGG 2138 Rh [981-999] 3'UTR

GGUUUCGACUGGUCCAGCU 1524 AGCUGGACCAGUCGAAACC 2139 Rh [1012-1030] 3'UTB

GAAUAAAACACUCAUCCCA 1525 UGGGAUGAGUGUUUUAUUC 2140 Rh [1057-1075] 3'UTB

GAGUUGCAGAUAUACCAAC 1526 GUUGGUAUAUCUGCAACUC 2141 Rh [2193-2211] 3'UTB

CUUCCUGUAUGGUGAUAUC 1527 GAUAUCACCAUACAGGAAG 2142 [2786-2804] 3'UTB

UUUGGUUCUCCAGUUCAAA 1528 UUUGAACUGGAGAACCAAA 2143 [3059-3077] 3'UTB

GCCUGCAUCAAGAGAAGUG 1529 CACUUCUCUUGAUGCAGGC 2144 Rt,Ms [875-893] ORF

GGCAACCCUAUCAAGAGGA 1530 UCCUCUUGAUAGGGUUGCC 2145 [488-506] ORF

AAGCGGUCAGUGAGAAGGA 1531 UCCUUCUCACUGACCGCUU 2146 [444-462] ORF

GUGGCUUUGGUGACACACU 1532 AGUGUGUCACCAAAGCCAC 2147 [2084-2102] 3'UTB

AGAUCUUGAUGACUUCCCU 1533 AGGGAAGUCAUCAAGAUCU 2148 Rh [2595-2613] 3'UTB

GAGACGUGGGUCCAAGGUC 1534 GACCUUGGACCCACGUCUC 2149 [1141-1159] 3'UTB UGACAUCAGCUGUAAUCAU 1535 AUGAUUACAGCUGAUGUCA 2150 [2863-2881] 3'UTB

GGGAUCUCCCAGCUGGGUU 1536 AACCCAGCUGGGAGAUCCC 2151 [1295-1313] 3'UTB

AGCACUUAGGGAUCUCCCA 1537 UGGGAGAUCCCUAAGUGCU 2152 R [1287-1305] 3'UTB

GUCUUUGGUUCUCCAGUUC 1538 GAACUGGAGAACCAAAGAC 2153 [3056-3074] 3'UTB

UAACCGUGCUGAGCAGAAA 1539 UUUCUGCUCAGCACGGUUA 2154 [3159-3177] 3'UTB

CUGGAUGGACUGGGUCACA 1540 UGUGACCCAGUCCAUCCAG 2155 Rh,Rb,Cw,Dg, [820-838] ORF

Rt,Ms,Pg

GUGCUGGGAACACACAAGA 1541 UCUUGUGUGUUCCCAGCAC 2156 [3533-3551] 3'UTB

AGUGGGAGCCUCCCUCUGA 1542 UCAGAGGGAGGCUCCCACU 2157 Rh [1593-1611] 3'UTB

GCAGGCAGCACUUAGGGAU 1543 AUCCCUAAGUGCUGCCUGC 2158 Rh [1281-1299] 3'UTB

UAUUGGACUUGCUGCCGUA 1544 UACGGCAGCAAGUCCAAUA 2159 [3423-3441] 3'UTB

GAUCUUGAUGACUUCCCUU 1545 AAGGGAAGUCAUCAAGAUC 2160 Rh [2596-2614] 3'UTB

ACGCCAGCUAAGCAUAGUA 1546 UACUAUGCUUAGCUGGCGU 2161 [2027-2045] 3'UTB

AGGACACUAUGGCCUGUUU 1547 AAACAGGCCAUAGUGUCCU 2162 [2122-2140] 3'UTB

GCCUGAACCACAGGUACCA 1548 UGGUACCUGUGGUUCAGGC 2163 Rh,Rb,Cw,Ms, Pg [729-747] ORF

UGGUUUGUUUUUGACAUCA 1549 UGAUGUCAAAAACAAACCA 2164 Rh [2852-2870] 3'UTB

GUGGCAGCUGACAGAGGAA 1550 UUCCUCUGUCAGCUGCCAC 2165 [3202-3220] 3'UTB

CCAUCAAUCCUAUUAAUCC 1551 GGAUUAAUAGGAUUGAUGG 2166 Rh [1564-1582] 3'UTB

GGACACUAUGGCCUGUUUU 1552 AAAACAGGCCAUAGUGUCC 2167 [2123-2141] 3'UTB

GACCUUCCGGUGCUGGGAA 1553 UUCCCAGCACCGGAAGGUC 2168 [3524-3542] 3'UTB

ACAUCCUGAGGACAGAAAA 1554 UUUUCUGUCCUCAGGAUGU 2169 Rh [1920-1938] 3'UTB

AUGUAAACAUACACACGCA 1555 UGCGUGUGUAUGUUUACAU 2170 Rh [2420-2438] 3'UTB

GCCUCCAAGGGUUUCGACU 1556 AGUCGAAACCCUUGGAGGC 2171 Rh [1003-1021] 3'UTB

CUGCAUCAAGAGAAGUGAC 1557 GUCACUUCUCUUGAUGCAG 2172 Rt,Ms [877-895] ORF

UGGAAGCAUUUGACCCAGA 1558 UCUGGGUCAAAUGCUUCCA 2173 [2955-2973] 3'UTB

AACACACAAGAGUUGUUGA 1559 UCAACAACUCUUGUGUGUU 2174 [3541-3559] 3'UTB

GGGAACUAGGGAACCUAUG 1560 CAUAGGUUCCCUAGUUCCC 2175 Rh [2264-2282] 3'UTB

AUACAGGCACAUUAUGUAA 1561 UUACAUAAUGUGCCUGUAU 2176 [2407-2425] 3'UTB

GACGUGGGUCCAAGGUCCU 1562 AGGACCUUGGACCCACGUC 2177 [1143-1161] 3'UTB

GGGUUAGGAUAGGAAGAAC 1563 GUUCUUCCUAUCCUAACCC 2178 [2321-2339] 3'UTB

GGACGAGUGCCUCUGGAUG 1564 CAUCCAGAGGCACUCGUCC 2179 Rh,Rb,Cw [808-826] ORF

AAAAAGCCUCCAAGGGUUU 1565 AAACCCUUGGAGGCUUUUU 2180 [998-1016] 3'UTR

CUUUGAGUAGGUUCGGUCU 1566 AGACCGAACCUACUCAAAG 2181 [3097-3115] 3'UTB

GGCAGACUGGGAGGGUAUC 1567 GAUACCCUCCCAGUCUGCC 2182 Rh [2620-2638] 3TJTB

GAAGGCUCUCCAUUUGGCA 1568 UGCCAAAUGGAGAGCCUUC 2183 [3271-3289] 3'UTB

GCCUCCCUCUGAGCCUUGU 1569 ACAAGGCUCAGAGGGAGGC 2184 Rh [1600-1618] 3'UTB

ACAAAACAGGUUAAGAAGA 1570 UCUUCUUAACCUGUUUUGU 2185 [3178-3196] 3'UTB

CCUAUGUGUUCCCUCAGUG 1571 CACUGAGGGAACACAUAGG 2186 [2277-2295] 3'UTB

AAAGGGCCUGAGAAGGAUA 1572 UAUCCUUCUCAGGCCCUUU 2187 [539-557] ORF

GCAGACUGCGCAUGUCUCU 1573 AGAGACAUGCGCAGUCUGC 2188 [3570-3588] 3'UTB

CCCUCCCAGGCUUAGUGUU 1574 AACACUAAGCCUGGGAGGG 2189 [1956-1974] 3'UTB

CCUCCAAGGGUUUCGACUG 1575 CAGUCGAAACCCUUGGAGG 2190 Rh [1004-1022] 3'UTB

GCUAGUUCUUGAAGGAGCC 1576 GGCUCCUUCAAGAACUAGC 2191 [1545-1563] 3'UTB

CUUGAUGACUUCCCUUUCU 1577 AGAAAGGGAAGUCAUCAAG 2192 Rh [2599-2617] 3'UTB

AUUAAUCCUCAGAAUUCCA 1578 UGGAAUUCUGAGGAUUAAU 2193 Rh [1575-1593] 3'UTB

GACCAGUCCAUGUGAUUUC 1579 GAAAUCACAUGGACUGGUC 2194 Rh [2711-2729] 3'UTB

AGUGAGAAGGAAGUGGACU 1580 AGUCCACUUCCUUCUCACU 2195 [452-470] ORF GAGAAUCUCUUGUUUCCUC 1581 GAGGAAACAAGAGAUUCUC 2196 [2358-2376] 3'UTB

GGCUCUCCAUUUGGCAUCG 1582 CGAUGCCAAAUGGAGAGCC 2197 [3274-3292] 3'UTB

CUUCUUGCCUGUUCUGGCA 1583 UGCCAGAACAGGCAAGAAG 2198 [1824-1842] 3'UTB

CUUUAUAUUUGAUCCACAC 1584 GUGUGGAUCAAAUAUAAAG 2199 [3128-3146] 3'UTB

GGGCCUGGAAAUGUGCAUU 1585 AAUGCACAUUUCCAGGCCC 2200 R [1320-1338] 3'UTB

CUUUGGUGACACACUCACU 1586 AGUGAGUGUGUCACCAAAG 2201 [2088-2106] 3'UTB

CAGCCUAGGAAGGGAAGGA 1587 UCCUUCCCUUCCUAGGCUG 2202 Rh [2053-2071] 3'UTB

CUCGCUGGACGUUGGAGGA 1588 UCCUCCAACGUCCAGCGAG 2203 Rt,Ms [601-619] ORF

GCUUUAUCCGGGCUUGUGU 1589 ACACAAGCCCGGAUAAAGC 2204 [1873-1891] 3'UTB

UGGACUCUGGAAACGACAU 1590 AUGUCGUUUCCAGAGUCCA 2205 Rh [465-483] ORF

GCAUCGUGGAAGCAUUUGA 1591 UCAAAUGCUUCCACGAUGC 2206 Rh [2949-2967] 3'UTB

CCUAAAGUUGGUAAGAUGU 1592 ACAUCUUACCAACUUUAGG 2207 Rh [2685-2703] 3'UTB

GUGGUCUUGCAAAAUGCUU 1593 AAGCAUUUUGCAAGACCAC 2208 [2466-2484] 3'UTB

CAAGGUCCCUUCCCUAGCU 1594 AGCUAGGGAAGGGACCUUG 2209 [1789-1807] 3'UTB

GCUUUGUAUCAUUCUUGAG 1595 CUCAAGAAUGAUACAAAGC 2210 [3592-3610] 3'UTB

GGGCUUCGAUCCUUGGGUG 1596 CACCCAAGGAUCGAAGCCC 2211 Rh [1198-1216] 3'UTB

UCAUAAUGGACCAGUCCAU 1597 AUGGACUGGUCCAUUAUGA 2212 Rh [2703-2721] 3'UTB

UAUAGUUUAAGAAGGCUCU 1598 AGAGCCUUCUUAAACUAUA 2213 [3261-3279] 3'UTB

UCGACAUCGAGGACCCAUA 1599 UAUGGGUCCUCGAUGUCGA 2214 Dg [945-963] ORF

ACUUCUUUCUCAGCCUCCA 1600 UGGAGGCUGAGAAAGAAGU 2215 [2104-2122] 3'UTB

AUUCUCAGAUGAUAGGUGA 1601 UCACCUAUCAUCUGAGAAU 2216 [2170-2188] 3'UTB

UGAGAAGGAAGUGGACUCU 1602 AGAGUCCACUUCCUUCUCA 2217 [454-472] ORF

CAAAGCACCUGUUAAGACU 1603 AGUCUUAACAGGUGCUUUG 2218 Rh [2523-2541] 3'UTR

GCGUUCCAGCCUCAGCUGA 1604 UCAGCUGAGGCUGGAACGC 2219 [1650-1668] 3'UTB

CCUGGGCGUGGUCUUGCAA 1605 UUGCAAGACCACGCCCAGG 2220 [2459-2477] 3'UTB

GUCUCUGAUGCUUUGUAUC 1606 GAUACAAAGCAUCAGAGAC 2221 [3583-3601] 3'UTB

CUGUGCCCUCCCAGGCUUA 1607 UAAGCCUGGGAGGGCACAG 2222 [1951-1969] 3'UTB

CCUCCAACCCAUAUAACAC 1608 GUGUUAUAUGGGUUGGAGG 2223 [2753-2771] 3'UTB

UUUGUAUCAUUCUUGAGCA 1609 UGCUCAAGAAUGAUACAAA 2224 [3594-3612] 3'UTB

GCCUUUAUAUUUGAUCCAC 1610 GUGGAUCAAAUAUAAAGGC 2225 [3126-3144] 3'UTB

AGGCCUACCAGGUCCCUUU 1611 AAAGGGACCUGGUAGGCCU 2226 Rh [1378-1396] 3'UTB

GUUCUAAGCACAGCUCUCU 1612 AGAGAGCUGUGCUUAGAAC 2227 [3310-3328] 3'UTB

CUGUGUUUUUUAUUACCCU 1613 AGGGUAAUAAAAAACACAG 2228 Rh [2889-2907] 3'UTB

CUAGGAAGGGAAGGAUUUU 1614 AAAAUCCUUCCCUUCCUAG 2229 Rh [2057-2075] 3'UTB

CAGAUGGGCUGCGAGUGCA 1615 UGCACUCGCAGCCCAUCUG 2230 Ck,Rb,Rt [746-764] ORF

CUGGCAUCAGGCACCUGGA 1616 UCCAGGUGCCUGAUGCCAG 2231 [1837-1855] 3'UTB

UGAUGCUUUGUAUCAUUCU 1617 AGAAUGAUACAAAGCAUCA 2232 [3588-3606] 3'UTB

AGUCCAGCCUAGGAAGGGA 1618 UCCCUUCCUAGGCUGGACU 2233 Rh [2049-2067] 3'UTB

CAAAGAUUACCUAGCUAAG 1619 CUUAGCUAGGUAAUCUUUG 2234 [2235-2253] 3'UTB

AGAAGGAAGUGGACUCUGG 1620 CCAGAGUCCACUUCCUUCU 2235 [456-474] ORF

UGUACAGUGACCUAAAGUU 1621 AACUUUAGGUCACUGUACA 2236 [2675-2693] 3'UTB

Table B2: 19-mer siTIMP2 Cross-Species

NO: NO:

UUCGCCUGCAUCAAGAGAA 2237 UUCUCUUGAUGCAGGCGAA 2354 Rh,Cw,Dg,Ms [872-890] ORF

GUGCAUUUUGCAGAAACUU 2238 AAGUUUCUGCAAAAUGCAC 2355 Rh,Rt,Ms [1332-1350] 3Ί

GGUACCAGAUGGGCUGCGA 2239 UCGCAGCCCAUCUGGUACC 2356 R ,Ck,Rb,Rt [741-759] ORF

GGUCUCGCUGGACGUUGGA 2240 UCCAACGUCCAGCGAGACC 2357 Rt,Ms [598-616] ORF

UCGCCUGCAUCAAGAGAAG 2241 CUUCUCUUGAUGCAGGCGA 2358 Rh,Cw,Dg,Ms [873-891] ORF

CUUCCUGGAAACAGCAUGA 2242 UCAUGCUGUUUCCAGGAAG 2359 Rh,Rb,Rt,Ms [1040-1058] 31

GGGCACCAGGCCAAGUUCU 2243 AGAACUUGGCCUGGUGCCC 2360 Rh,Rb,Rt,Ms [854-872] ORF

CCAGAAGAAGAGCCUGAAC 2244 GUUCAGGCUCUUCUUCUGG 2361 Rh,Rb,Cw,Ms,Pg [718-736] ORF

UGGACGUUGGAGGAAAGAA 2245 UUCUUUCCUCCAACGUCCA 2362 Rt,Ms [606-624] ORF

GGGCUGCGAGUGCAAGAUC 2246 GAUCUUGCACUCGCAGCCC 2363 Ck,Rb,Rt [751-769] ORF

CCACCCAGAAGAAGAGCCU 2247 AGGCUCUUCUUCUGGGUGG 2364 Rh,Ck,Cw,Rt,Ms,Pg [714-732] ORF

AUGGGCUGCGAGUGCAAGA 2248 UCUUGCACUCGCAGCCCAU 2365 Ck,Rb,Rt [749-767] ORF

AUGGACUGGGUCACAGAGA 2249 UCUCUGUGACCCAGUCCAU 2366 Rh,Rt,Ms,Pg [824-842] ORF

UGGGCUGCGAGUGCAAGAU 2250 AUCUUGCACUCGCAGCCCA 2367 Ck,Rb,Rt [750-768] ORF

ACGUUGGAGGAAAGAAGGA 2251 UCCUUCUUUCCUCCAACGU 2368 Rt,Ms [609-627] ORF

GACGUUGGAGGAAAGAAGG 2252 CCUUCUUUCCUCCAACGUC 2369 Rt,Ms [608-626] ORF

AGGCCAAGUUCUUCGCCUG 2253 CAGGCGAAGAACUUGGCCU 2370 Rh,Rb,Cw,Dg,Ms [861-879] ORF

GAAGAAGAGCCUGAACCAC 2254 GUGGUUCAGGCUCUUCUUC 2371 Rh,Rb,Cw,Ms,Pg [721-739] ORF

GCACCCGCAACAGGCGUUU 2255 AAACGCCUGUUGCGGGUGC 2372 Cw,Dg,Rt,Ms [397-415] ORF

UUCUUCGCCUGCAUCAAGA 2256 UCUUGAUGCAGGCGAAGAA 2373 Rh,Rb,Cw,Dg,Ms [869-887] ORF

GAGCCUGAACCACAGGUAC 2257 GUACCUGUGGUUCAGGCUC 2374 Rh,Rb,Cw,Ms,Pg [727-745] ORF

CUUCGCCUGCAUCAAGAGA 2258 UCUCUUGAUGCAGGCGAAG 2375 Rh,Rb,Cw,Dg,Ms [871-889] ORF

UGGAAACAGCAUGAAUAAA 2259 UUUAUUCAUGCUGUUUCCA 2376 Rh,Rb,Rt,Ms [1045-1063] 3Ί

GACAUCCCUUCCUGGAAAC 2260 GUUUCCAGGAAGGGAUGUC 2377 Rh,Rt,Ms [1033-1051] 31

GUUCUUCGCCUGCAUCAAG 2261 CUUGAUGCAGGCGAAGAAC 2378 Rh,Rb,Cw,Dg,Ms [868-886] ORF

AAGUUCUUCGCCUGCAUCA 2262 UGAUGCAGGCGAAGAACUU 2379 Rh,Rb,Cw,Dg,Ms [866-884] ORF

CCCUUCCUGGAAACAGCAU 2263 AUGCUGUUUCCAGGAAGGG 2380 Rh,Rb,Rt,Ms [1038-1056] 31

CGCUCGGCCUCCUGCUGCU 2264 AGCAGCAGGAGGCCGAGCG 2381 Dg,Rt,Ms [333-351] ORF

UGAACCACAGGUACCAGAU 2265 AUCUGGUACCUGUGGUUCA 2382 Rh,Rb,Cw,Ms,Pg [732-750] ORF

CUGAACCACAGGUACCAGA 2266 UCUGGUACCUGUGGUUCAG 2383 Rh,Rb,Cw,Ms,Pg [731-749] ORF

CAGAAGAAGAGCCUGAACC 2267 GGUUCAGGCUCUUCUUCUG 2384 Rh,Rb,Cw,Ms,Pg [719-737] ORF

UCCUGGAAACAGCAUGAAU 2268 AUUCAUGCUGUUUCCAGGA 2385 Rh,Rb,Rt,Ms [1042-1060] 31

GAUGGACUGGGUCACAGAG 2269 CUCUGUGACCCAGUCCAUC 2386 Rh,Rt,Ms,Pg [823-841] ORF

GCCGACGCCUGCAGCUGCU 2270 AGCAGCUGCAGGCGUCGGC 2387 Cw,Dg,Rt,Ms [371-389] ORF

CAGGCGUUUUGCAAUGCAG 2271 CUGCAUUGCAAAACGCCUG 2388 Cw,Rt,Ms [407-425] ORF

UCAAGCAGAUAAAGAUGUU 2272 AACAUCUUUAUCUGCUUGA 2389 Cw,Dg,Rt,Ms,Pg [519-537] ORF

GAACCACAGGUACCAGAUG 2273 CAUCUGGUACCUGUGGUUC 2390 Rh,Rb,Cw,Rt,Ms,Pg [733-751] ORF

CACCCAGAAGAAGAGCCUG 2274 CAGGCUCUUCUUCUGGGUG 2391 Rh,Ck,Cw,Rt,Ms,Pg [715-733] ORF

CCUUCCUGGAAACAGCAUG 2275 CAUGCUGUUUCCAGGAAGG 2392 Rh,Rb,Rt,Ms [1039-1057] 31

CAACAGGCGUUUUGCAAUG 2276 CAUUGCAAAACGCCUGUUG 2393 Cw,Rt,Ms [404-422] ORF

CACAGGUACCAGAUGGGCU 2277 AGCCCAUCUGGUACCUGUG 2394 Rh,Rb,Cw,Rt,Ms,Pg [737-755] ORF

UCCCUUCCUGGAAACAGCA 2278 UGCUGUUUCCAGGAAGGGA 2395 Rh,Rb,Rt,Ms [1037-1055] 31

UGAGAUCAAGCAGAUAAAG 2279 CUUUAUCUGCUUGAUCUCA 2396 Rh,Cw,Dg,Rt,Ms [514-532] ORF

GGUGCACCCGCAACAGGCG 2280 CGCCUGUUGCGGGUGCACC 2397 Cw,Dg,Rt,Ms [394-412] ORF

AGUGCCUCUGGAUGGACUG 2281 CAGUCCAUCCAGAGGCACU 2398 Rh,Rb,Cw,Dg,Rt,Ms [813-831] ORF

AAGCAGAUAAAGAUGUUCA 2282 UGAACAUCUUUAUCUGCUU 2399 Cw,Dg,Rt,Ms,Pg [521-539] ORF

UGCACCCGCAACAGGCGUU 2283 AACGCCUGUUGCGGGUGCA 2400 Cw,Dg,Rt,Ms [396-414] ORF

CACCCGCAACAGGCGUUUU 2284 AAAACGCCUGUUGCGGGUG 2401 Cw,Rt,Ms [398-416] ORF

CUGGACGUUGGAGGAAAGA 2285 UCUUUCCUCCAACGUCCAG 2402 Rt,Ms [605-623] ORF

AUCCCUUCCUGGAAACAGC 2286 GCUGUUUCCAGGAAGGGAU 2403 Rh,Rb,Rt,Ms [1036-1054] 31

ACAGGCGUUUUGCAAUGCA 2287 UGCAUUGCAAAACGCCUGU 2404 Cw,Rt,Ms [406-424] ORF

GAUGGGCUGCGAGUGCAAG 2288 CUUGCACUCGCAGCCCAUC 2405 Ck,Rb,Rt [748-766] ORF

AGCCUGAACCACAGGUACC 2289 GGUACCUGUGGUUCAGGCU 2406 Rh,Rb,Cw,Ms,Pg [728-746] ORF CCUCUGGAUGGACUGGGUC 2290 GACCCAGUCCAUCCAGAGG 2407 Rh,Rb,Cw,Dg,Rt,Ms [817-835] ORF

,Pg

CGGGCACCAGGCCAAGUUC 2291 GAACUUGGCCUGGUGCCCG 2408 Rh,Rb,Rt,Ms [853-871] ORF

CAGGCCAAGUUCUUCGCCU 2292 AGGCGAAGAACUUGGCCUG 2409 Rh,Rb,Cw,Dg,Ms [860-878] ORF

CAAGUUCUUCGCCUGCAUC 2293 GAUGCAGGCGAAGAACUUG 2410 Rh,Rb,Cw,Dg,Ms [865-883] ORF

ACUUCAUCGUGCCCUGGGA 2294 UCCCAGGGCACGAUGAAGU 2411 Rh,Rb,Cw,Dg,Pg [684-702] ORF

ACAUCCCUUCCUGGAAACA 2295 UGUUUCCAGGAAGGGAUGU 2412 Rh,Rt,Ms [1034-1052] 31

UACCAGAUGGGCUGCGAGU 2296 ACUCGCAGCCCAUCUGGUA 2413 Rh,Ck,Rb,Rt [743-761] ORF

GGCCAAGUUCUUCGCCUGC 2297 GCAGGCGAAGAACUUGGCC 2414 Rh,Rb,Cw,Dg,Ms [862-880] ORF

CCAGAUGGGCUGCGAGUGC 2298 GCACUCGCAGCCCAUCUGG 2415 Rh,Ck,Rb,Rt [745-763] ORF

GUGACUUCAUCGUGCCCUG 2299 CAGGGCACGAUGAAGUCAC 2416 Rh,Rb,Cw,Dg,Pg [681-699] ORF

UCGCUGGACGUUGGAGGAA 2300 UUCCUCCAACGUCCAGCGA 2417 Rt,Ms [602-620] ORF

AUCAAGCAGAUAAAGAUGU 2301 ACAUCUUUAUCUGCUUGAU 2418 Cw,Dg,Rt,Ms,Pg [518-536] ORF

GUACCAGAUGGGCUGCGAG 2302 CUCGCAGCCCAUCUGGUAC 2419 Rh,Ck,Rb,Rt [742-760] ORF

CGAGUGCCUCUGGAUGGAC 2303 GUCCAUCCAGAGGCACUCG 2420 Rh,Rb,Cw,Dg,Rt,Ms [811-829] ORF

UCUGGAUGGACUGGGUCAC 2304 GUGACCCAGUCCAUCCAGA 2421 Rh,Rb,Cw,Dg,Rt,Ms [819-837] ORF

,Pg

ACCAGAUGGGCUGCGAGUG 2305 CACUCGCAGCCCAUCUGGU 2422 Rh,Ck,Rb,Rt [744-762] ORF

ACAGGUACCAGAUGGGCUG 2306 CAGCCCAUCUGGUACCUGU 2423 Rh,Rb,Cw,Rt,Ms,Pg [738-756] ORF

GAAGAGCCUGAACCACAGG 2307 CCUGUGGUUCAGGCUCUUC 2424 Rh,Rb,Cw,Ms,Pg [724-742] ORF

GUGCACCCGCAACAGGCGU 2308 ACGCCUGUUGCGGGUGCAC 2425 Cw,Dg,Rt,Ms [395-413] ORF

UGGAUGGACUGGGUCACAG 2309 CUGUGACCCAGUCCAUCCA 2426 Rh,Rt,Ms,Pg [821-839] ORF

CAAGCAGAUAAAGAUGUUC 2310 GAACAUCUUUAUCUGCUUG 2427 Cw,Dg,Rt,Ms,Pg [520-538] ORF

GUGCCUCUGGAUGGACUGG 2311 CCAGUCCAUCCAGAGGCAC 2428 Rh,Rb,Cw,Dg,Rt,Ms [814-832] ORF

CAUCCCUUCCUGGAAACAG 2312 CUGUUUCCAGGAAGGGAUG 2429 Rh,Rb,Rt,Ms [1035-1053] 31

CACCAGGCCAAGUUCUUCG 2313 CGAAGAACUUGGCCUGGUG 2430 Rh,Rb,Cw,Ms [857-875] ORF

CCUGAACCACAGGUACCAG 2314 CUGGUACCUGUGGUUCAGG 2431 Rh,Rb,Cw,Ms,Pg [730-748] ORF

AACCACAGGUACCAGAUGG 2315 CCAUCUGGUACCUGUGGUU 2432 Rh,Rb,Cw,Rt,Ms,Pg [734-752] ORF

GUCUCGCUGGACGUUGGAG 2316 CUCCAACGUCCAGCGAGAC 2433 Rt,Ms [599-617] ORF

AGAGUUUAUCUACACGGCC 2317 GGCCGUGUAGAUAAACUCU 2434 Dg,Ms,Pg [559-577] ORF

UUCCUGGAAACAGCAUGAA 2318 UUCAUGCUGUUUCCAGGAA 2435 Rh,Rb,Rt,Ms [1041-1059] 31

GAUAAAGAUGUUCAAAGGG 2319 CCCUUUGAACAUCUUUAUC 2436 Dg,Rt,Ms [526-544] ORF

UCUUCGCCUGCAUCAAGAG 2320 CUCUUGAUGCAGGCGAAGA 2437 Rh,Rb,Cw,Dg,Ms [870-888] ORF

UGGCGCUCGGCCUCCUGCU 2321 AGCAGGAGGCCGAGCGCCA 2438 Dg,Rt,Ms [330-348] ORF

CCCGGUGCACCCGCAACAG 2322 CUGUUGCGGGUGCACCGGG 2439 Cw,Dg,Rt,Ms [391-409] ORF

CCCGCAACAGGCGUUUUGC 2323 GCAAAACGCCUGUUGCGGG 2440 Cw,Rt,Ms [400-418] ORF

CAGGGCCAAAGCGGUCAGU 2324 ACUGACCGCUUUGGCCCUG 2441 Rb,Dg [436-454] ORF

AAGAGCCUGAACCACAGGU 2325 ACCUGUGGUUCAGGCUCUU 2442 Rh,Rb,Cw,Ms,Pg [725-743] ORF

ACCACAGGUACCAGAUGGG 2326 CCCAUCUGGUACCUGUGGU 2443 Rh,Rb,Cw,Rt,Ms,Pg [735-753] ORF

CAGGUACCAGAUGGGCUGC 2327 GCAGCCCAUCUGGUACCUG 2444 Rh,Rb,Cw,Dg,Rt,Ms [739-757] ORF

,Pg

CGGUGCACCCGCAACAGGC 2328 GCCUGUUGCGGGUGCACCG 2445 Cw,Dg,Rt,Ms [393-411] ORF

GCUCGGCCUCCUGCUGCUG 2329 CAGCAGCAGGAGGCCGAGC 2446 Dg,Rt,Ms [334-352] ORF

GACGCCUGCAGCUGCUCCC 2330 GGGAGCAGCUGCAGGCGUC 2447 Cw,Dg,Rt,Ms [374-392] ORF

ACCCGCAACAGGCGUUUUG 2331 CAAAACGCCUGUUGCGGGU 2448 Cw,Rt,Ms [399-417] ORF

CCGGUGCACCCGCAACAGG 2332 CCUGUUGCGGGUGCACCGG 2449 Cw,Dg,Rt,Ms [392-410] ORF

UCUCGCUGGACGUUGGAGG 2333 CCUCCAACGUCCAGCGAGA 2450 Rt,Ms [600-618] ORF

AACAGCAUGAAUAAAACAC 2334 GUGUUUUAUUCAUGCUGUU 2451 Rh,Rt,Ms [1049-1067] 31

CCACAGGUACCAGAUGGGC 2335 GCCCAUCUGGUACCUGUGG 2452 Rh,Rb,Cw,Rt,Ms,Pg [736-754] ORF

CCGACGCCUGCAGCUGCUC 2336 GAGCAGCUGCAGGCGUCGG 2453 Cw,Dg,Rt,Ms [372-390] ORF

UUCAUCGUGCCCUGGGACA 2337 UGUCCCAGGGCACGAUGAA 2454 Rh,Rb,Cw,Dg,Pg [686-704] ORF

CUUCAUCGUGCCCUGGGAC 2338 GUCCCAGGGCACGAUGAAG 2455 Rh,Rb,Cw,Dg,Pg [685-703] ORF

CGACGCCUGCAGCUGCUCC 2339 GGAGCAGCUGCAGGCGUCG 2456 Cw,Dg,Rt,Ms [373-391] ORF

UGCCUCUGGAUGGACUGGG 2340 CCCAGUCCAUCCAGAGGCA 2457 Rh,Rb,Cw,Dg,Rt,Ms [815-833] ORF 105 ACCAGGCCAAGUUCUUCGC 2341 GCGAAGAACUUGGCCUGGU 2458 Rh,Rb,Cw,Ms [858-876] ORF

106 AGGUACCAGAUGGGCUGCG 2342 CGCAGCCCAUCUGGUACCU 2459 R ,Ck,Rb,Rt [740-758] ORF

107 CUCGGCCUCCUGCUGCUGG 2343 CCAGCAGCAGGAGGCCGAG 2460 Dg,Rt [335-353] ORF

108 AACAGGCGUUUUGCAAUGC 2344 GCAUUGCAAAACGCCUGUU 2461 Cw,Rt,Ms [405-423] ORF

109 UCGGCCUCCUGCUGCUGGC 2345 GCCAGCAGCAGGAGGCCGA 2462 Dg,Rt [336-354] ORF

110 CCAGGCCAAGUUCUUCGCC 2346 GGCGAAGAACUUGGCCUGG 2463 Rh,Rb,Cw,Dg,Ms [859-877] ORF

111 UGUGACUUCAUCGUGCCCU 2347 AGGGCACGAUGAAGUCACA 2464 Rh,Rb,Cw,Dg,Pg [680-698] ORF

112 GACUUCAUCGUGCCCUGGG 2348 CCCAGGGCACGAUGAAGUC 2465 Rh,Rb,Cw,Dg,Pg [683-701] ORF

113 CUGUGACUUCAUCGUGCCC 2349 GGGCACGAUGAAGUCACAG 2466 Rh,Rb,Cw,Dg,Pg [679-697] ORF

114 UGACUUCAUCGUGCCCUGG 2350 CCAGGGCACGAUGAAGUCA 2467 Rh,Rb,Cw,Dg,Pg [682-700] ORF

616 GCAGGAGUUUCUCGACAUC 2351 GAUGUCGAGAAACUCCUGC 2468 Dg,Ck [934-952] ORF

617 GCACCACCCAGAAGAAGAG 2352 CUCUUCUUCUGGGUGGUGC 2469 Pg,Rh [711-729] ORF

618 AGCUCUGACAUCCCUUCCU 2353 AGGAAGGGAUGUCAGAGCU 2470 Rh [1027-1045] 31

Table B3: Preferred 19-mer siTIMP2

siTIMP2 pNo. Sense (5'>3') SEQ Antisense (5'>3') SEQ length position

ID ID

NO: NO:

siTIMP2 p4 GGCUGCGAGUGCAAGAUCA 2471 UGAUCUUGCACUCGCAGCC 2524 19 [752-770] ORF siTIMP2 pl6 GUAUGAGAUCAAGCAGAUA 2472 UAUCUGCUUGAUCUCAUAC 2525 19 [511-529] ORF siTIMP2 pl7 GAGGAAAGAAGGAAUAUCU 2473 AGAUAUUCCUUCUUUCCUC 2526 19 [615-633] ORF siTIMP2 pl8 CCUGCAUCAAGAGAAGUGA 2474 UCACUUCUCUUGAUGCAGG 2527 19 [876-894] ORF siTIMP2 p20 AUGAGAUCAAGCAGAUAAA 2475 UUUAUCUGCUUGAUCUCAU 2528 19 [513-531] ORF siTIMP2 p24 GUUGGAGGAAAGAAGGAAU 2476 AUUCCUUCUUUCCUCCAAC 2529 19 [611-629] ORF siTIMP2 p25 ACUGGGUCACAGAGAAGAA 2477 UUCUUCUCUGUGACCCAGU 2530 19 [828-846] ORF siTIMP2 p27 CUCUGGAUGGACUGGGUCA 2478 UGACCCAGUCCAUCCAGAG 2531 19 [818-836] ORF siTIMP2 p29 GGCGUUUUGCAAUGCAGAU 2479 AUCUGCAUUGCAAAACGCC 2532 19 [409-427] ORF siTIMP2 p30 GCCUCUGGAUGGACUGGGU 2480 ACCCAGUCCAUCCAGAGGC 2533 19 [816-834] ORF siTIMP2 p33 GGAGGAAAGAAGGAAUAUC 2481 GAUAUUCCUUCUUUCCUCC 2534 19 [614-632] ORF siTIMP2 p35 GGACUGGGUCACAGAGAAG 2482 CUUCUCUGUGACCCAGUCC 2535 19 [826-844] ORF siTIMP2 p37 GGACGUUGGAGGAAAGAAG 2483 CUUCUUUCCUCCAACGUCC 2536 19 [607-625] ORF siTIMP2 p38 CGUUGGAGGAAAGAAGGAA 2484 UUCCUUCUUUCCUCCAACG 2537 19 [610-628] ORF siTIMP2_p39 CUGACAUCCCUUCCUGGAA 2485 UUCCAGGAAGGGAUGUCAG 2538 19 [1031-1049]3TJT ] siTIMP2 p40 UGACAUCCCUUCCUGGAAA 2486 UUUCCAGGAAGGGAUGUCA 2539 19 [1032-1050]3'UT1 siTIMP2 p41 AGAUGGGCUGCGAGUGCAA 2487 UUGCACUCGCAGCCCAUCU 2540 19 [747-765] ORF siTIMP2 p44 GGGUCUCGCUGGACGUUGG 2488 CCAACGUCCAGCGAGACCC 2541 19 [597-615] ORF siTIMP2 p46 GAGUGCCUCUGGAUGGACU 2489 AGUCCAUCCAGAGGCACUC 2542 19 [812-830] ORF siTIMP2 p51 AGCAGAUAAAGAUGUUCAA 2490 UUGAACAUCUUUAUCUGCU 2543 19 [522-540] ORF siTIMP2 p55 GCAACAGGCGUUUUGCAAU 2491 AUUGCAAAACGCCUGUUGC 2544 19 [403-421] ORF siTIMP2 p61 GCUGGACGUUGGAGGAAAG 2492 CUUUCCUCCAACGUCCAGC 2545 19 [604-622] ORF siTIMP2 p62 UGUGCAUUUUGCAGAAACU 2493 AGUUUCUGCAAAAUGCACA 2546 19 [1331-1349]3'UT1 siTIMP2 p64 GGCACCAGGCCAAGUUCUU 2494 AAGAACUUGGCCUGGUGCC 2547 19 [855-873] ORF siTIMP2 p65 GCCUGCAUCAAGAGAAGUG 2495 CACUUCUCUUGAUGCAGGC 2548 19 [875-893] ORF siTIMP2 p67 CUGGAUGGACUGGGUCACA 2496 UGUGACCCAGUCCAUCCAG 2549 19 [820-838] ORF siTIMP2 p68 CUGCAUCAAGAGAAGUGAC 2497 GUCACUUCUCUUGAUGCAG 2550 19 [877-895] ORF siTIMP2 p69 CUCGCUGGACGUUGGAGGA 2498 UCCUCCAACGUCCAGCGAG 2551 19 [601-619] ORF siTIMP2 p71 CAGAUGGGCUGCGAGUGCA 2499 UGCACUCGCAGCCCAUCUG 2552 19 [746-764] ORF siTIMP2 p75 GUGCAUUUUGCAGAAACUU 2500 AAGUUUCUGCAAAAUGCAC 2553 19 [1332-1350]3'UT1 siTIMP2 p76 GGUACCAGAUGGGCUGCGA 2501 UCGCAGCCCAUCUGGUACC 2554 19 [741-759] ORF siTIMP2 p78 GGUCUCGCUGGACGUUGGA 2502 UCCAACGUCCAGCGAGACC 2555 19 [598-616] ORF siTIMP2 p79 CUUCCUGGAAACAGCAUGA 2503 UCAUGCUGUUUCCAGGAAG 2556 19 [1040-1058]3TJT] siTIMP2 p82 GGGCACCAGGCCAAGUUCU 2504 AGAACUUGGCCUGGUGCCC 2557 19 [854-872] ORF siTIMP2 p83 GUCACAGAGAAGAACAUCA 2505 UGAUGUUCUUCUCUGUGAC 2558 19 [833-851] ORF siTIMP2 p84 AGGAGUUUCUCGACAUCGA 2506 UCGAUGUCGAGAAACUCCU 2559 19 [936-954] ORF siTIMP2_p85 CCCAGAAGAAGAGCCUGAA 2507 UUCAGGCUCUUCUUCUGGG 2560 19 [717-735] ORF siTIMP2 p86 GGGUCACAGAGAAGAACAU 2508 AUGUUCUUCUCUGUGACCC 2561 19 [831-849] ORF siTIMP2 p87 CCAAGUUCUUCGCCUGCAU 2509 AUGCAGGCGAAGAACUUGG 2562 19 [864-882] ORF siTIMP2 p88 AGCACCACCCAGAAGAAGA 2510 UCUUCUUCUGGGUGGUGCU 2563 19 [710-728] ORF siTIMP2 p89 GUUUUGCAAUGCAGAUGUA 2511 UACAUCUGCAUUGCAAAAC 2564 19 [412-430] ORF siTIMP2 p90 AGCAGGAGUUUCUCGACAU 2512 AUGUCGAGAAACUCCUGCU 2565 19 [933-951] ORF siTIMP2 p91 GGAGUUUCUCGACAUCGAG 2513 CUCGAUGUCGAGAAACUCC 2566 19 [937-955] ORF siTIMP2 p92 GCCUGAACCACAGGUACCA 2514 UGGUACCUGUGGUUCAGGC 2567 19 [729-747] ORF siTIMP2 p93 UUCGCCUGCAUCAAGAGAA 2515 UUCUCUUGAUGCAGGCGAA 2568 19 [872-890] ORF siTIMP2 p94 AGAGCCUGAACCACAGGUA 2516 UACCUGUGGUUCAGGCUCU 2569 19 [726-744] ORF siTIMP2 p95 GCAGGAGUUUCUCGACAUC 2517 GAUGUCGAGAAACUCCUGC 2570 19 [934-952] ORF siTIMP2 p96 GCACCACCCAGAAGAAGAG 2518 CUCUUCUUCUGGGUGGUGC 2571 19 [711-729] ORF siTIMP2_p97 GGACGAGUGCCUCUGGAUG 2519 CAUCCAGAGGCACUCGUCC 2572 19 [808-826] ORF siTIMP2 p98 GACUGGUCCAGCUCUGACA 2520 UGUCAGAGCUGGACCAGUC 2573 19 [1018-1036]3'UTI siTIMP2 p99 ACAUCACCCUCUGUGACUU 2521 AAGUCACAGAGGGUGAUGU 2574 19 [669-687] ORF siTIMP2 plOO CCGGACGAGUGCCUCUGGA 2522 UCCAGAGGCACUCGUCCGG 2575 19 [806-824] ORF siTIMP2 plOl UCGCCUGCAUCAAGAGAAG 2523 CUUCUCUUGAUGCAGGCGA 2576 19 [873-891] ORF

SiTIMP2 pl02 GGAAGAACUUUCUCGGUAA 1007 UUACCGAGAAAGUUCUUCC 1622 19 [2332-2350]3'UTl

Table B4: 19 mer siTIMP2 with lowest predicted OT effect

Table B5: 18-mer siTIMP2

CCAACUUCUGCUUGUAUU 2621 AAUACAAGCAGAAGUUGG 3656 R [2207-2224] 3'UI

CGAUAUACAGGCACAUUA 2622 UAAUGUGCCUGUAUAUCG 3657 [2403-2420] 3'UI

GGCCUAUGCAGGUGGAUU 2623 AAUCCACCUGCAUAGGCC 3658 R [2985-3002] 3'UI

GGGAGGGUAUCCAGGAAU 2624 AUUCCUGGAUACCCUCCC 3659 Rh [2628-2645] 3'UI

CCUAUUAAUCCUCAGAAU 2625 AUUCUGAGGAUUAAUAGG 3660 Rh [1572-1589] 3'UI

GGGAGACGUGGGUCCAAG 2626 CUUGGACCCACGUCUCCC 3661 [1139-1156] 3'UI

GCUCAAAUACCUUCACAA 2627 UUGUGAAGGUAUUUGAGC 3662 [3224-3241] 3'UI

CCAAGGUCCUCAUCCCAU 2628 AUGGGAUGAGGACCUUGG 3663 [1152-1169] 3'UI

AGUAAGAAGUCCAGCCUA 2629 UAGGCUGGACUUCUUACU 3664 Rh [2042-2059] 3'UI

GGACUGGGUCACAGAGAA 2630 UUCUCUGUGACCCAGUCC 3665 Rh,Rt,Ms,Pg [826-843] ORF

AGCUAAGCAUAGUAAGAA 2631 UUCUUACUAUGCUUAGCU 3666 [2032-2049] 3'UI

GGUUUGUUUUUGACAUCA 2632 UGAUGUCAAAAACAAACC 3667 Rh [2853-2870] 3'UI

GGAGUUUCUCGACAUCGA 2633 UCGAUGUCGAGAAACUCC 3668 Ck,Dg [937-954] ORF

GAGUCUUUUUGGUCUGCA 2634 UGCAGACCAAAAAGACUC 3669 [1667-1684] 3'UI

AGGAGAAUCUCUUGUUUC 2635 GAAACAAGAGAUUCUCCU 3670 [2356-2373] 3'UI

CGGUAAUGAUAAGGAGAA 2636 UUCUCCUUAUCAUUACCG 3671 [2345-2362] 3'UI

GGUAUUAGACUUGCACUU 2637 AAGUGCAAGUCUAAUACC 3672 [2913-2930] 3'UI

CGGUCAGUGAGAAGGAAG 2638 CUUCCUUCUCACUGACCG 3673 [447-464] ORF

GCGGUCAGUGAGAAGGAA 2639 UUCCUUCUCACUGACCGC 3674 [446-463] ORF

UCCUGAAGCCAGUGAUAU 2640 AUAUCACUGGCUUCAGGA 3675 [2301-2318] 3'UI

AGAAGAGCCUGAACCACA 2641 UGUGGUUCAGGCUCUUCU 3676 Rh,Rb,Cw, Ms,Pg [723-740] ORF

GAAAGAAGGAAUAUCUCA 2642 UGAGAUAUUCCUUCUUUC 3677 [618-635] ORF

GCCGUAAUUUAAAGCUCU 2643 AGAGCUUUAAAUUACGGC 3678 [3436-3453] 3'UI

CGUGGACAAUAAACAGUA 2644 UACUGUUUAUUGUCCACG 3679 [3624-3641] 3'UI

GUGAAUUCUCAGAUGAUA 2645 UAUCAUCUGAGAAUUCAC 3680 [2166-2183] 3'UI

GGAACACACAAGAGUUGU 2646 ACAACUCUUGUGUGUUCC 3681 [3539-3556] 3'UI

GAGGAUCCAGUAUGAGAU 2647 AUCUCAUACUGGAUCCUC 3682 Rh,Rb [502-519] ORF

UGAGAAGGAUAUAGAGUU 2648 AACUCUAUAUCCUUCUCA 3683 [547-564] ORF

GCGUGGUCUUGCAAAAUG 2649 CAUUUUGCAAGACCACGC 3684 [2464-2481] 3'UI

CUGUUUUAAGAGACAUCU 2650 AGAUGUCUCUUAAAACAG 3685 Rh [2135-2152] 3'UI

CCCUCAGUGUGGUUUCCU 2651 AGGAAACCACACUGAGGG 3686 [2287-2304] 3'UI

GAGUUGCAGAUAUACCAA 2652 UUGGUAUAUCUGCAACUC 3687 Rh [2193-2210] 3'UI

CUGGGAACACACAAGAGU 2653 ACUCUUGUGUGUUCCCAG 3688 [3536-3553] 3'UI

GCUGAGUCUUUUUGGUCU 2654 AGACCAAAAAGACUCAGC 3689 Rh [1664-1681] 3'UI

CUGCAUCAAGAGAAGUGA 2655 UCACUUCUCUUGAUGCAG 3690 Rt,Ms [877-894] ORF

GAGGAAAGAAGGAAUAUC 2656 GAUAUUCCUUCUUUCCUC 3691 Rt [615-632] ORF

GCUGGACGUUGGAGGAAA 2657 UUUCCUCCAACGUCCAGC 3692 Rt,Ms [604-621] ORF

GGUGUGGCCUUUAUAUUU 2658 AAAUAUAAAGGCCACACC 3693 [3120-3137] 3'UI

GCAUUUUGCAGAAACUUU 2659 AAAGUUUCUGCAAAAUGC 3694 Rh [1334-1351] 3'UI

GGACCAGUCCAUGUGAUU 2660 AAUCACAUGGACUGGUCC 3695 Rh [2710-2727] 3'UI

CACCUUAGCCUGUUCUAU 2661 AUAGAACAGGCUAAGGUG 3696 Rh [2492-2509] 3'UI

UGAUAAGGAGAAUCUCUU 2662 AAGAGAUUCUCCUUAUCA 3697 Rh [2351-2368] 3'UI

CUCAAAGACUGACAGCCA 2663 UGGCUGUCAGUCUUUGAG 3698 Rh [1981-1998] 3'UI

GGGACAUGGCCCUUGUUU 2664 AAACAAGGGCCAUGUCCC 3699 [1407-1424] 3'UI

CCAUCAAUCCUAUUAAUC 2665 GAUUAAUAGGAUUGAUGG 3700 Rh [1564-1581] 3'UI

GAACCAGUGGCUAGUUCU 2666 AGAACUAGCCACUGGUUC 3701 [1536-1553] 3'UI

AGACAUGGUUGUGGGUCU 2667 AGACCCACAACCAUGUCU 3702 [1118-1135] 3'UI

GUUUAAGAAGGCUCUCCA 2668 UGGAGAGCCUUCUUAAAC 3703 [3265-3282] 3'UI

CUUCCUGUAUGGUGAUAU 2669 AUAUCACCAUACAGGAAG 3704 [2786-2803] 3'UI 94 GGACCUGGUCAGCACAGA 2670 UCUGUGCUGACCAGGUCC 3705 R [2580-2597] 3'UI

95 GAGACGUGGGUCCAAGGU 2671 ACCUUGGACCCACGUCUC 3706 [1141-1158] 3'UI

96 GGAACCAGUGGCUAGUUC 2672 GAACUAGCCACUGGUUCC 3707 [1535-1552] 3'UI

97 GGGCAGCCUGGAACCAGU 2673 ACUGGUUCCAGGCUGCCC 3708 [1526-1543] 3'UI

98 GCAUCAGGCACCUGGAUU 2674 AAUCCAGGUGCCUGAUGC 3709 [1840-1857] 3'UI

99 GGCGUUUUGCAAUGCAGA 2675 UCUGCAUUGCAAAACGCC 3710 Cw,Rt,Ms [409-426] ORF

100 CCUCCAACCCAUAUAACA 2676 UGUUAUAUGGGUUGGAGG 3711 [2753-2770] 3'UI

101 GCCUUUAUAUUUGAUCCA 2677 UGGAUCAAAUAUAAAGGC 3712 [3126-3143] 3'UI

102 GCACAGAUCUUGAUGACU 2678 AGUCAUCAAGAUCUGUGC 3713 Rh [2591-2608] 3'UI

103 GUCCCUUUCAUCUUGAGA 2679 UCUCAAGAUGAAAGGGAC 3714 Rh [1389-1406] 3'UI

104 GGAAGCAUUUGACCCAGA 2680 UCUGGGUCAAAUGCUUCC 3715 [2956-2973] 3'UI

105 GGCAGACUGGGAGGGUAU 2681 AUACCCUCCCAGUCUGCC 3716 Rh [2620-2637] 3'UI

106 GCUUUGUAUCAUUCUUGA 2682 UCAAGAAUGAUACAAAGC 3717 [3592-3609] 3'UI

107 GAGGAAGCCGCUCAAAUA 2683 UAUUUGAGCGGCUUCCUC 3718 [3215-3232] 3'UI

108 CCUUCUCCUUUUAGACAU 2684 AUGUCUAAAAGGAGAAGG 3719 [1106-1123] 3'UI

109 GGGCGUGGUCUUGCAAAA 2685 UUUUGCAAGACCACGCCC 3720 [2462-2479] 3'UI

110 GCUGAGCAGAAAACAAAA 2686 UUUUGUUUUCUGCUCAGC 3721 [3166-3183] 3'UI

111 GACCAGUCCAUGUGAUUU 2687 AAAUCACAUGGACUGGUC 3722 Rh [2711-2728] 3'UI

112 GAGAAUCUCUUGUUUCCU 2688 AGGAAACAAGAGAUUCUC 3723 [2358-2375] 3'UI

113 UCCUAUUAAUCCUCAGAA 2689 UUCUGAGGAUUAAUAGGA 3724 Rh [1571-1588] 3'UI

114 CACAGAGAAGAACAUCAA 2690 UUGAUGUUCUUCUCUGUG 3725 Rh [835-852] ORF

115 GCCUGCAUCAAGAGAAGU 2691 ACUUCUCUUGAUGCAGGC 3726 Rt,Ms [875-892] ORF

116 GGUGACACACUCACUUCU 2692 AGAAGUGAGUGUGUCACC 3727 [2092-2109] 3'UI

117 AGGAAAGAAGGAAUAUCU 2693 AGAUAUUCCUUCUUUCCU 3728 Rt [616-633] ORF

118 CCACCUGUGUUGUAAAGA 2694 UCUUUACAACACAGGUGG 3729 Rh [2377-2394] 3'UI

119 GUCCAUGUGAUUUCAGUA 2695 UACUGAAAUCACAUGGAC 3730 Rh [2716-2733] 3'UI

120 AGUGGACUCUGGAAACGA 2696 UCGUUUCCAGAGUCCACU 3731 Rh [463-480] ORF

121 GACAUCAGCUGUAAUCAU 2697 AUGAUUACAGCUGAUGUC 3732 [2864-2881] 3'UI

122 GCCUGUUCUAUUCAGCGG 2698 CCGCUGAAUAGAACAGGC 3733 [2499-2516] 3'UI

123 AGAUCAAGCAGAUAAAGA 2699 UCUUUAUCUGCUUGAUCU 3734 Cw,Dg,Rt,Ms [516-533] ORF

124 GUCUCUGAUGCUUUGUAU 2700 AUACAAAGCAUCAGAGAC 3735 [3583-3600] 3'UI

125 GUUCAAAGGGCCUGAGAA 2701 UUCUCAGGCCCUUUGAAC 3736 [535-552] ORF

126 GGGAACUAGGGAACCUAU 2702 AUAGGUUCCCUAGUUCCC 3737 Rh [2264-2281] 3'UI

127 AUGAUAAGGAGAAUCUCU 2703 AGAGAUUCUCCUUAUCAU 3738 [2350-2367] 3'UI

128 CUUAGCCUGUUCUAUUCA 2704 UGAAUAGAACAGGCUAAG 3739 Rh [2495-2512] 3'UI

129 GUAAUGAUAAGGAGAAUC 2705 GAUUCUCCUUAUCAUUAC 3740 [2347-2364] 3'UI

130 GGACGAGUGCCUCUGGAU 2706 AUCCAGAGGCACUCGUCC 3741 Rh,Rb,Cw [808-825] ORF

131 CACAAUAAAUAGUGGCAA 2707 UUGCCACUAUUUAUUGUG 3742 [3237-3254] 3'UI

132 GUUGGAGGAAAGAAGGAA 2708 UUCCUUCUUUCCUCCAAC 3743 Rt [611-628] ORF

133 AGGUAUUAGACUUGCACU 2709 AGUGCAAGUCUAAUACCU 3744 [2912-2929] 3'UI

134 ACACAAGAGUUGUUGAAA 2710 UUUCAACAACUCUUGUGU 3745 [3544-3561] 3'UI

135 CCUAUGUGUUCCCUCAGU 2711 ACUGAGGGAACACAUAGG 3746 [2277-2294] 3'UI

136 CAAUGCAGAUGUAGUGAU 2712 AUCACUACAUCUGCAUUG 3747 [418-435] ORF

137 GAAUAUGAAGUCUGAGAC 2713 GUCUCAGACUUCAUAUUC 3748 [3509-3526] 3'UI

138 CCUCCAAGGGUUUCGACU 2714 AGUCGAAACCCUUGGAGG 3749 Rh [1004-1021] 3'UI

139 GUGGUUUCCUGAAGCCAG 2715 CUGGCUUCAGGAAACCAC 3750 [2295-2312] 3'UI

140 UGUUCUAUUCAGCGGCAA 2716 UUGCCGCUGAAUAGAACA 3751 [2502-2519] 3'UI

141 GAUGAUAGGUGAACCUGA 2717 UCAGGUUCACCUAUCAUC 3752 [2177-2194] 3'UI 142 GCCUCAGCUGAGUCUUUU 2718 AAAAGACUCAGCUGAGGC 3753 R [1658-1675] 3'UI

143 AGGUGAAUUCUCAGAUGA 2719 UCAUCUGAGAAUUCACCU 3754 [2164-2181] 3'UI

144 AGGGAGACGUGGGUCCAA 2720 UUGGACCCACGUCUCCCU 3755 [1138-1155] 3'UI

145 AGAAGGAAGUGGACUCUG 2721 CAGAGUCCACUUCCUUCU 3756 [456-473] ORF

146 GGAAGCCGCUCAAAUACC 2722 GGUAUUUGAGCGGCUUCC 3757 [3217-3234] 3'UI

147 GCUGUACAGUGACCUAAA 2723 UUUAGGUCACUGUACAGC 3758 [2673-2690] 3'UI

148 GGAUAGGAAGAACUUUCU 2724 AGAAAGUUCUUCCUAUCC 3759 [2327-2344] 3'UI

149 CCCUUCUCCUUUUAGACA 2725 UGUCUAAAAGGAGAAGGG 3760 [1105-1122] 3'UI

150 CCACCUUAGCCUGUUCUA 2726 UAGAACAGGCUAAGGUGG 3761 Rh [2491-2508] 3'UI

151 GGGCUUCGAUCCUUGGGU 2727 ACCCAAGGAUCGAAGCCC 3762 Rh [1198-1215] 3'UI

152 AGUGUUCCCUCCCUCAAA 2728 UUUGAGGGAGGGAACACU 3763 [1969-1986] 3'UI

153 GAACUUUCUCGGUAAUGA 2729 UCAUUACCGAGAAAGUUC 3764 [2336-2353] 3'UI

154 GAGAAGGAAGUGGACUCU 2730 AGAGUCCACUUCCUUCUC 3765 [455-472] ORF

155 CAUCAAUCCUAUUAAUCC 2731 GGAUUAAUAGGAUUGAUG 3766 Rh [1565-1582] 3'UI

156 GCAGGAGUUUCUCGACAU 2732 AUGUCGAGAAACUCCUGC 3767 Ck,Dg [934-951] ORF

157 GGGUUAGGAUAGGAAGAA 2733 UUCUUCCUAUCCUAACCC 3768 [2321-2338] 3'UI

158 CUGAUGCUUUGUAUCAUU 2734 AAUGAUACAAAGCAUCAG 3769 [3587-3604] 3'UI

159 CAGCCUCAGCUGAGUCUU 2735 AAGACUCAGCUGAGGCUG 3770 Rh [1656-1673] 3'UI

160 GGCCUGUUUUAAGAGACA 2736 UGUCUCUUAAAACAGGCC 3771 Rh [2132-2149] 3'UI

161 CAUACACACGCAAUGAAA 2737 UUUCAUUGCGUGUGUAUG 3772 Rh [2427-2444] 3'UI

162 GCACCACCCAGAAGAAGA 2738 UCUUCUUCUGGGUGGUGC 3773 Rh,Pg [711-728] ORF

163 CUCUGAUGCUUUGUAUCA 2739 UGAUACAAAGCAUCAGAG 3774 [3585-3602] 3'UI

164 GGGCUUUCUGCAUGUGAC 2740 GUCACAUGCAGAAAGCCC 3775 [2011-2028] 3'UI

165 CUCUGGAAACGACAUUUA 2741 UAAAUGUCGUUUCCAGAG 3776 Rh [469-486] ORF

166 GAUUGAGUUGCACAGCUU 2742 AAGCUGUGCAACUCAAUC 3777 [1854-1871] 3'UI

167 GUCAGUGAGAAGGAAGUG 2743 CACUUCCUUCUCACUGAC 3778 [449-466] ORF

168 CCAGCUUGCAGGAGGAAU 2744 AUUCCUCCUGCAAGCUGG 3779 [1723-1740] 3'UI

169 CCCUGUUCGCUUCCUGUA 2745 UACAGGAAGCGAACAGGG 3780 [2777-2794] 3'UI

170 CAUGGGUCCAAAUUAAUA 2746 UAUUAAUUUGGACCCAUG 3781 [1074-1091] 3'UI

171 CUCUGUUGAUUUUGUUUC 2747 GAAACAAAAUCAACAGAG 3782 [3450-3467] 3'UI

172 GGAAGGAUUUUGGAGGUA 2748 UACCUCCAAAAUCCUUCC 3783 Rh [2065-2082] 3'UI

173 GGAACUAGGGAACCUAUG 2749 CAUAGGUUCCCUAGUUCC 3784 Rh [2265-2282] 3'UI

174 CCUGGAUUGAGUUGCACA 2750 UGUGCAACUCAAUCCAGG 3785 [1850-1867] 3'UI

175 GCCUGGAAAUGUGCAUUU 2751 AAAUGCACAUUUCCAGGC 3786 Rh [1322-1339] 3'UI

176 GGCCAAAGCGGUCAGUGA 2752 UCACUGACCGCUUUGGCC 3787 [439-456] ORF

177 ACUUCUGCUUGUAUUUCU 2753 AGAAAUACAAGCAGAAGU 3788 Rh [2210-2227] 3'UI

178 CCCUUUCUAGGGCAGACU 2754 AGUCUGCCCUAGAAAGGG 3789 Rh [2610-2627] 3'UI

179 CCUGGUCAGCACAGAUCU 2755 AGAUCUGUGCUGACCAGG 3790 Rh [2583-2600] 3'UI

180 GGGUCCAAGGUCCUCAUC 2756 GAUGAGGACCUUGGACCC 3791 [1148-1165] 3'UI

181 CUGUAUGGUGAUAUCAUA 2757 UAUGAUAUCACCAUACAG 3792 [2790-2807] 3'UI

182 UGGACUUGCUGCCGUAAU 2758 AUUACGGCAGCAAGUCCA 3793 [3426-3443] 3'UI

183 CCUGUUCGCUUCCUGUAU 2759 AUACAGGAAGCGAACAGG 3794 [2778-2795] 3'UI

184 GUGACACACUCACUUCUU 2760 AAGAAGUGAGUGUGUCAC 3795 [2093-2110] 3'UI

185 GGUGGAUUCCUUCAGGUC 2761 GACCUGAAGGAAUCCACC 3796 Rh [2995-3012] 3'UI

186 CCCAUCAAUCCUAUUAAU 2762 AUUAAUAGGAUUGAUGGG 3797 Rh [1563-1580] 3'UI

187 GCUAGUUCUUGAAGGAGC 2763 GCUCCUUCAAGAACUAGC 3798 [1545-1562] 3'UI

188 GUGGGUCCAAGGUCCUCA 2764 UGAGGACCUUGGACCCAC 3799 [1146-1163] 3'UI

189 GCUUCCAAAGCCACCUUA 2765 UAAGGUGGCUUUGGAAGC 3800 Rh [2481-2498] 3'UI 190 GGUCACAGAGAAGAACAU 2766 AUGUUCUUCUCUGUGACC 3801 R [832-849] ORF

191 GCAUCAAGAGAAGUGACG 2767 CGUCACUUCUCUUGAUGC 3802 [879-896] ORF

192 UGGUCUUGCAAAAUGCUU 2768 AAGCAUUUUGCAAGACCA 3803 [2467-2484] 3'UI

193 AGCAGGAGUUUCUCGACA 2769 UGUCGAGAAACUCCUGCU 3804 Ck,Dg [933-950] ORF

194 GUUGAAAGUUGACAAGCA 2770 UGCUUGUCAACUUUCAAC 3805 [3555-3572] 3'UI

195 GGUCUUGCAAAAUGCUUC 2771 GAAGCAUUUUGCAAGACC 3806 [2468-2485] 3'UI

196 GUGUUUAUGCUGGAAUAU 2772 AUAUUCCAGCAUAAACAC 3807 [3497-3514] 3'UI

197 GCAGAAAACAAAACAGGU 2773 ACCUGUUUUGUUUUCUGC 3808 [3171-3188] 3'UI

198 ACCUAAAGUUGGUAAGAU 2774 AUCUUACCAACUUUAGGU 3809 [2684-2701] 3'UI

199 AGCAGACUGCGCAUGUCU 2775 AGACAUGCGCAGUCUGCU 3810 [3569-3586] 3'UI

200 AGCCUGUUCUAUUCAGCG 2776 CGCUGAAUAGAACAGGCU 3811 [2498-2515] 3'UI

201 GGCAGCACUUAGGGAUCU 2777 AGAUCCCUAAGUGCUGCC 3812 Rh [1284-1301] 3'UI

202 CAUUUAUGGCAACCCUAU 2778 AUAGGGUUGCCAUAAAUG 3813 [481-498] ORF

203 GGCUCUCCAUUUGGCAUC 2779 GAUGCCAAAUGGAGAGCC 3814 [3274-3291] 3'UI

204 UGUUUCUGCUGAUUGUUU 2780 AAACAAUCAGCAGAAACA 3815 [2823-2840] 3'UI

205 GCUGCGAGUGCAAGAUCA 2781 UGAUCUUGCACUCGCAGC 3816 Rt [753-770] ORF

206 CUUUCUCGGUAAUGAUAA 2782 UUAUCAUUACCGAGAAAG 3817 [2339-2356] 3'UI

207 GUUUCCGUUUGGAUUUUU 2783 AAAAAUCCAAACGGAAAC 3818 [3463-3480] 3'UI

208 GGGCUGCGAGUGCAAGAU 2784 AUCUUGCACUCGCAGCCC 3819 Ck,Rb,Rt [751-768] ORF

209 CCUGAGUUGCAGAUAUAC 2785 GUAUAUCUGCAACUCAGG 3820 Rh [2190-2207] 3'UI

210 GUUUCCUGAAGCCAGUGA 2786 UCACUGGCUUCAGGAAAC 3821 [2298-2315] 3'UI

211 GGAUUUUGGAGGUAGGUG 2787 CACCUACCUCCAAAAUCC 3822 Rh [2069-2086] 3'UI

212 GCAAAAAAAGCCUCCAAG 2788 CUUGGAGGCUUUUUUUGC 3823 [994-1011] 3'UTI

213 CCAAGUUCUUCGCCUGCA 2789 UGCAGGCGAAGAACUUGG 3824 Rh,Rb,Cw,Dg,Ms [864-881] ORF

214 GUUCCCUCAGUGUGGUUU 2790 AAACCACACUGAGGGAAC 3825 [2284-2301] 3'UI

215 GGAGCACUGUGUUUAUGC 2791 GCAUAAACACAGUGCUCC 3826 [3489-3506] 3'UI

216 UAAGAAGGCUCUCCAUUU 2792 AAAUGGAGAGCCUUCUUA 3827 [3268-3285] 3'UI

217 GCGUUUUCAUGCUGUACA 2793 UGUACAGCAUGAAAACGC 3828 Rh [2663-2680] 3'UI

218 GGUUCGGUCUGAAAGGUG 2794 CACCUUUCAGACCGAACC 3829 [3106-3123] 3'UI

219 GAUUACCUAGCUAAGAAA 2795 UUUCUUAGCUAGGUAAUC 3830 [2239-2256] 3'UI

220 CUUUCAUCUUGAGAGGGA 2796 UCCCUCUCAAGAUGAAAG 3831 [1393-1410] 3'UI

221 AGGGCAGCCUGGAACCAG 2797 CUGGUUCCAGGCUGCCCU 3832 [1525-1542] 3'UI

222 GGGACACGCGGCUUCCCU 2798 AGGGAAGCCGCGUGUCCC 3833 [1228-1245] 3'UI

223 CCUAGGAAGGGAAGGAUU 2799 AAUCCUUCCCUUCCUAGG 3834 Rh [2056-2073] 3'UI

224 CCAAGGGCAGCCUGGAAC 2800 GUUCCAGGCUGCCCUUGG 3835 [1522-1539] 3'UI

225 AUAUGAAGUCUGAGACCU 2801 AGGUCUCAGACUUCAUAU 3836 [3511-3528] 3'UI

226 GGACUCUGGAAACGACAU 2802 AUGUCGUUUCCAGAGUCC 3837 Rh [466-483] ORF

227 CCUGAAGCCAGUGAUAUG 2803 CAUAUCACUGGCUUCAGG 3838 [2302-2319] 3'UI

228 GGACUUGCUGCCGUAAUU 2804 AAUUACGGCAGCAAGUCC 3839 [3427-3444] 3'UI

229 ACGGCAAGAUGCACAUCA 2805 UGAUGUGCAUCUUGCCGU 3840 Dg,Pg [657-674] ORF

230 CAAGAGUUGUUGAAAGUU 2806 AACUUUCAACAACUCUUG 3841 [3547-3564] 3'UI

231 GGUCAGCACAGAUCUUGA 2807 UCAAGAUCUGUGCUGACC 3842 Rh [2586-2603] 3'UI

232 AGGGAACUAGGGAACCUA 2808 UAGGUUCCCUAGUUCCCU 3843 Rh [2263-2280] 3'UI

233 CGGACGAGUGCCUCUGGA 2809 UCCAGAGGCACUCGUCCG 3844 Rh,Rb,Cw [807-824] ORF

234 CUCCAGUUCAAAUUAUUG 2810 CAAUAAUUUGAACUGGAG 3845 [3066-3083] 3'UI

235 CAUGGUUGUGGGUCUGGA 2811 UCCAGACCCACAACCAUG 3846 [1121-1138] 3'UI

236 AGGUGAACCUGAGUUGCA 2812 UGCAACUCAGGUUCACCU 3847 Rh [2183-2200] 3'UI

237 GGUGAGGUCCUGUCCUGA 2813 UCAGGACAGGACCUCACC 3848 Rh [1742-1759] 3'UI 238 CAGUGUGGUUUCCUGAAG 2814 CUUCAGGAAACCACACUG 3849 [2291-2308] 3'UI

239 GAAGAAGAGCCUGAACCA 2815 UGGUUCAGGCUCUUCUUC 3850 Rh,Rb,Cw,Ms,Pg [721-738] ORF

240 GGUAGGUGGCUUUGGUGA 2816 UCACCAAAGCCACCUACC 3851 R [2079-2096] 3'UI

241 CCCUCAAGGUCCCUUCCC 2817 GGGAAGGGACCUUGAGGG 3852 [1785-1802] 3'UI

242 UCGCCUGCAUCAAGAGAA 2818 UUCUCUUGAUGCAGGCGA 3853 Rh,Cw,Dg,Ms [873-890] ORF

243 AGCAUUUGACCCAGAGUG 2819 CACUCUGGGUCAAAUGCU 3854 [2959-2976] 3'UI

244 GGGUCUUGCUGUGCCCUC 2820 GAGGGCACAGCAAGACCC 3855 Rh [1943-1960] 3'UI

245 GCCUCCUGCUGCUGGCGA 2821 UCGCCAGCAGCAGGAGGC 3856 Dg [339-356] ORF

246 CAGGCUUAGUGUUCCCUC 2822 GAGGGAACACUAAGCCUG 3857 [1962-1979] 3'UI

247 CCAGAAGAAGAGCCUGAA 2823 UUCAGGCUCUUCUUCUGG 3858 Rh,Rb,Cw,Ms,Pg [718-735] ORF

248 GACCCAGAGUGGAACGCG 2824 CGCGUUCCACUCUGGGUC 3859 [2966-2983] 3'UI

249 AGGUGUGGCCUUUAUAUU 2825 AAUAUAAAGGCCACACCU 3860 [3119-3136] 3'UI

250 CAGUGGGAGCCUCCCUCU 2826 AGAGGGAGGCUCCCACUG 3861 Rh [1592-1609] 3'UI

251 UGGUUCUCCAGUUCAAAU 2827 AUUUGAACUGGAGAACCA 3862 [3061-3078] 3'UI

252 GGUUAAGAAGAGCCGGGU 2828 ACCCGGCUCUUCUUAACC 3863 [3186-3203] 3'UI

253 AAGGAGAAUCUCUUGUUU 2829 AAACAAGAGAUUCUCCUU 3864 [2355-2372] 3'UI

254 UCUGAUGCUUUGUAUCAU 2830 AUGAUACAAAGCAUCAGA 3865 [3586-3603] 3'UI

255 CCAGGUCCCUUUCAUCUU 2831 AAGAUGAAAGGGACCUGG 3866 Rh [1385-1402] 3'UI

256 CACCCUCUGUGACUUCAU 2832 AUGAAGUCACAGAGGGUG 3867 Rh,Cw,Ms [673-690] ORF

257 CCCUUGGUAGGUAUUAGA 2833 UCUAAUACCUACCAAGGG 3868 [2904-2921] 3'UI

258 CUAUGUGUUCCCUCAGUG 2834 CACUGAGGGAACACAUAG 3869 [2278-2295] 3'UI

259 GAGCCUGAACCACAGGUA 2835 UACCUGUGGUUCAGGCUC 3870 Rh,Rb,Cw,Ms,Pg [727-744] ORF

260 GGCAAGUGCUCCCAUCGC 2836 GCGAUGGGAGCACUUGCC 3871 [1460-1477] 3'UI

261 GAAUUCCAGUGGGAGCCU 2837 AGGCUCCCACUGGAAUUC 3872 Rh [1586-1603] 3'UI

262 GCAAUGCAGAUGUAGUGA 2838 UCACUACAUCUGCAUUGC 3873 [417-434] ORF

263 CCUGAGAAGGAUAUAGAG 2839 CUCUAUAUCCUUCUCAGG 3874 [545-562] ORF

264 ACCUGAGUUGCAGAUAUA 2840 UAUAUCUGCAACUCAGGU 3875 Rh [2189-2206] 3'UI

265 GACCUAAAGUUGGUAAGA 2841 UCUUACCAACUUUAGGUC 3876 [2683-2700] 3'UI

266 GUCUUUGGUUCUCCAGUU 2842 AACUGGAGAACCAAAGAC 3877 [3056-3073] 3'UI

267 GCCUAGGAAGGGAAGGAU 2843 AUCCUUCCCUUCCUAGGC 3878 Rh [2055-2072] 3'UI

268 CGCAUGUCUCUGAUGCUU 2844 AAGCAUCAGAGACAUGCG 3879 [3578-3595] 3'UI

269 CAAUCCUAUUAAUCCUCA 2845 UGAGGAUUAAUAGGAUUG 3880 Rh [1568-1585] 3'UI

270 AGCCUCAGCUGAGUCUUU 2846 AAAGACUCAGCUGAGGCU 3881 Rh [1657-1674] 3'UI

271 GCUCUGUUGAUUUUGUUU 2847 AAACAAAAUCAACAGAGC 3882 [3449-3466] 3'UI

272 GUGGGAGCCUCCCUCUGA 2848 UCAGAGGGAGGCUCCCAC 3883 Rh [1594-1611] 3'UI

273 GACUCUGGAAACGACAUU 2849 AAUGUCGUUUCCAGAGUC 3884 Rh [467-484] ORF

274 AGCAUAGUAAGAAGUCCA 2850 UGGACUUCUUACUAUGCU 3885 [2037-2054] 3'UI

275 CAGAGGAAGCCGCUCAAA 2851 UUUGAGCGGCUUCCUCUG 3886 [3213-3230] 3'UI

276 GUUGGUAAGAUGUCAUAA 2852 UUAUGACAUCUUACCAAC 3887 Rh [2691-2708] 3'UI

277 CUAUUUUCAUCCUGCAAG 2853 CUUGCAGGAUGAAAAUAG 3888 [3333-3350] 3'UI

278 AGUUGCAGAUAUACCAAC 2854 GUUGGUAUAUCUGCAACU 3889 Rh [2194-2211] 3'UI

279 AAUGAUAAGGAGAAUCUC 2855 GAGAUUCUCCUUAUCAUU 3890 [2349-2366] 3'UI

280 GGAGAAUCUCUUGUUUCC 2856 GGAAACAAGAGAUUCUCC 3891 [2357-2374] 3'UI

281 GUAAGAUGUCAUAAUGGA 2857 UCCAUUAUGACAUCUUAC 3892 Rh [2695-2712] 3'UI

282 CCUUGGUAGGUAUUAGAC 2858 GUCUAAUACCUACCAAGG 3893 [2905-2922] 3'UI

283 GGCUGGGACACGCGGCUU 2859 AAGCCGCGUGUCCCAGCC 3894 [1224-1241] 3'UI

284 CACAAGAGUUGUUGAAAG 2860 CUUUCAACAACUCUUGUG 3895 [3545-3562] 3'UI

285 GAGGGUCGUUGCAAGACU 2861 AGUCUUGCAACGACCCUC 3896 [1353-1370] 3'UI 286 AAACGACAUUUAUGGCAA 2862 UUGCCAUAAAUGUCGUUU 3897 [475-492] ORF

287 UGAUGACUUCCCUUUCUA 2863 UAGAAAGGGAAGUCAUCA 3898 R [2601-2618] 3'UI

288 GGCUUAGUGUUCCCUCCC 2864 GGGAGGGAACACUAAGCC 3899 [1964-1981] 3'UI

289 CAGAGAAGAACAUCAACG 2865 CGUUGAUGUUCUUCUCUG 3900 Rh [837-854] ORF

290 CCAGCCUCAGCUGAGUCU 2866 AGACUCAGCUGAGGCUGG 3901 Rh [1655-1672] 3'Ul

291 GGGACACCCUGAGCACCA 2867 UGGUGCUCAGGGUGUCCC 3902 Rh,Pg [699-716] ORF

292 CUCACUUCUUUCUCAGCC 2868 GGCUGAGAAAGAAGUGAG 3903 [2101-2118] 3'Ul

293 GACAUCCCUUCCUGGAAA 2869 UUUCCAGGAAGGGAUGUC 3904 Rh,Rt,Ms [1033-1050] 3'Ul

294 CCUGGCAAGUGCUCCCAU 2870 AUGGGAGCACUUGCCAGG 3905 [1457-1474] 3'Ul

295 AGAAAUGGGAGCGAGAAA 2871 UUUCUCGCUCCCAUUUCU 3906 [1619-1636] 3'Ul

296 GCAAUGAAACCGAAGCUU 2872 AAGCUUCGGUUUCAUUGC 3907 [2436-2453] 3'Ul

297 AUGUCAUAAUGGACCAGU 2873 ACUGGUCCAUUAUGACAU 3908 Rh [2700-2717] 3'Ul

298 UGUGGUUUCCUGAAGCCA 2874 UGGCUUCAGGAAACCACA 3909 [2294-2311] 3'Ul

299 GAUAUACAGGCACAUUAU 2875 AUAAUGUGCCUGUAUAUC 3910 [2404-2421] 3'Ul

300 AAAAAAGCCUCCAAGGGU 2876 ACCCUUGGAGGCUUUUUU 3911 [997-1014] 3'UTI

301 GUAUGGUGAUAUCAUAUG 2877 CAUAUGAUAUCACCAUAC 3912 [2792-2809] 3'Ul

302 CCUGUGCUGUGUUUUUUA 2878 UAAAAAACACAGCACAGG 3913 Rh [2883-2900] 3'Ul

303 AGGCCAAGUUCUUCGCCU 2879 AGGCGAAGAACUUGGCCU 3914 Rh,Rb,Cw,Dg,Ms [861-878] ORF

304 UGCAGAUAUACCAACUUC 2880 GAAGUUGGUAUAUCUGCA 3915 Rh [2197-2214] 3'Ul

305 AGAAGGAAUAUCUCAUUG 2881 CAAUGAGAUAUUCCUUCU 3916 [621-638] ORF

306 GAAGGAUUUUGGAGGUAG 2882 CUACCUCCAAAAUCCUUC 3917 Rh [2066-2083] 3'Ul

307 GCGGCUUCCCUCCCAGUC 2883 GACUGGGAGGGAAGCCGC 3918 [1235-1252] 3'Ul

308 CUCAGAAUUCCAGUGGGA 2884 UCCCACUGGAAUUCUGAG 3919 Rh [1582-1599] 3'Ul

309 GAUGGACUGGGUCACAGA 2885 UCUGUGACCCAGUCCAUC 3920 Rh,Rt,Ms,Pg [823-840] ORF

310 AUAUCUCAUUGCAGGAAA 2886 UUUCCUGCAAUGAGAUAU 3921 [628-645] ORF

311 ACAUUUAUGGCAACCCUA 2887 UAGGGUUGCCAUAAAUGU 3922 [480-497] ORF

312 UUAAGAAGGCUCUCCAUU 2888 AAUGGAGAGCCUUCUUAA 3923 [3267-3284] 3'Ul

313 GCAAAAUGCUUCCAAAGC 2889 GCUUUGGAAGCAUUUUGC 3924 Rh [2474-2491] 3'Ul

314 CUCCCUCAAAGACUGACA 2890 UGUCAGUCUUUGAGGGAG 3925 Rh [1977-1994] 3'Ul

315 GCCUCUGGAUGGACUGGG 2891 CCCAGUCCAUCCAGAGGC 3926 Rh,Rb,Cw,Dg,Rt,Ms [816-833] ORF

316 CGUUGGUCUUUUAACCGU 2892 ACGGUUAAAAGACCAACG 3927 [3148-3165] 3'Ul

317 AGGAAUAUCUCAUUGCAG 2893 CUGCAAUGAGAUAUUCCU 3928 [624-641] ORF

318 GAGUUUAUCUACACGGCC 2894 GGCCGUGUAGAUAAACUC 3929 Ms,Pg [560-577] ORF

319 UUUUCAUCCUGCAAGCAA 2895 UUGCUUGCAGGAUGAAAA 3930 [3336-3353] 3'Ul

320 CAAAGCGGUCAGUGAGAA 2896 UUCUCACUGACCGCUUUG 3931 [442-459] ORF

321 GUUUCUGCUGAUUGUUUU 2897 AAAACAAUCAGCAGAAAC 3932 [2824-2841] 3'Ul

322 AAAGGUGAAUUCUCAGAU 2898 AUCUGAGAAUUCACCUUU 3933 [2162-2179] 3'Ul

323 GAGUGCCUCUGGAUGGAC 2899 GUCCAUCCAGAGGCACUC 3934 Rh,Rb,Cw,Dg,Rt,Ms [812-829] ORF

324 CAAAGAUUACCUAGCUAA 2900 UUAGCUAGGUAAUCUUUG 3935 [2235-2252] 3'Ul

325 CCAGCUCUGACAUCCCUU 2901 AAGGGAUGUCAGAGCUGG 3936 Rh [1025-1042] 3'Ul

326 GUUCUUCGCCUGCAUCAA 2902 UUGAUGCAGGCGAAGAAC 3937 Rh,Rb,Cw,Dg,Ms [868-885] ORF

327 GGCUCCUGUGCGUGGUAC 2903 GUACCACGCACAGGAGCC 3938 Rh [896-913] ORF

328 UAGACAUGGUUGUGGGUC 2904 GACCCACAACCAUGUCUA 3939 [1117-1134] 3'Ul

329 AGAAGUCCAGCCUAGGAA 2905 UUCCUAGGCUGGACUUCU 3940 Rh [2046-2063] 3'Ul

330 GCAAGACUGUGUAGCAGG 2906 CCUGCUACACAGUCUUGC 3941 Rh [1363-1380] 3'Ul

331 GCUCUCUUCUCCUAUUUU 2907 AAAAUAGGAGAAGAGAGC 3942 [3322-3339] 3'Ul

332 GGCAAGAUGCACAUCACC 2908 GGUGAUGUGCAUCUUGCC 3943 Rh,Dg [659-676] ORF

333 GAAGAACUUUCUCGGUAA 2909 UUACCGAGAAAGUUCUUC 3944 Rh [2333-2350] 3'Ul

334 AGAGUUGUUGAAAGUUGA 2910 UCAACUUUCAACAACUCU 3945 [3549-3566] 3'Ul 335 GUAUAUACAACUCCACCA 2911 UGGUGGAGUUGUAUAUAC 3946 R [2731-2748] 3'UI

336 GCUUAGUGUUCCCUCCCU 2912 AGGGAGGGAACACUAAGC 3947 [1965-1982] 3'UI

337 GCUCUGACAUCCCUUCCU 2913 AGGAAGGGAUGUCAGAGC 3948 Rh [1028-1045] 3'UI

338 CCCAUGGGUCCAAAUUAA 2914 UUAAUUUGGACCCAUGGG 3949 [1072-1089] 3'UI

339 UGGCCAACUGC AAAAAAA 2915 UUUUUUUGCAGUUGGCCA 3950 [985-1002] 3'UTI

340 GGACACUAUGGCCUGUUU 2916 AAACAGGCCAUAGUGUCC 3951 [2123-2140] 3'UI

341 GCCAGCUAAGCAUAGUAA 2917 UUACUAUGCUUAGCUGGC 3952 [2029-2046] 3'UI

342 CCAAGGGUUUCGACUGGU 2918 ACCAGUCGAAACCCUUGG 3953 Rh [1007-1024] 3'UI

343 AGAUGCACAUCACCCUCU 2919 AGAGGGUGAUGUGCAUCU 3954 Rh [663-680] ORF

344 GGCAGGGCCUGGAAAUGU 2920 ACAUUUCCAGGCCCUGCC 3955 [1316-1333] 3'UI

345 GGUCCUCAUCCCAUCCUC 2921 GAGGAUGGGAUGAGGACC 3956 Rh [1156-1173] 3'UI

346 CGACAUUUAUGGCAACCC 2922 GGGUUGCCAUAAAUGUCG 3957 [478-495] ORF

347 GCCUUGUAGAAAUGGGAG 2923 CUCCCAUUUCUACAAGGC 3958 Rh [1612-1629] 3'UI

348 CAGUCCAUGUGAUUUCAG 2924 CUGAAAUCACAUGGACUG 3959 Rh [2714-2731] 3'UI

349 GGAGACGUGGGUCCAAGG 2925 CCUUGGACCCACGUCUCC 3960 [1140-1157] 3'UI

350 CAGCUUUGCUUUAUCCGG 2926 CCGGAUAAAGCAAAGCUG 3961 [1866-1883] 3'UI

351 UGCAAGCAACUCAAAAUA 2927 UAUUUUGAGUUGCUUGCA 3962 [3345-3362] 3'UI

352 CCUUUCUAGGGCAGACUG 2928 CAGUCUGCCCUAGAAAGG 3963 Rh [2611-2628] 3'UI

353 CCUGGAAAUGUGCAUUUU 2929 AAAAUGCACAUUUCCAGG 3964 Rh [1323-1340] 3'UI

354 AUGGCAACCCUAUCAAGA 2930 UCUUGAUAGGGUUGCCAU 3965 [486-503] ORF

355 GCCAUUGCUUCUUGCCUG 2931 CAGGCAAGAAGCAAUGGC 3966 [1817-1834] 3'UI

356 GGAACCUAUGUGUUCCCU 2932 AGGGAACACAUAGGUUCC 3967 Rh [2273-2290] 3'UI

357 GAUAUACCAACUUCUGCU 2933 AGCAGAAGUUGGUAUAUC 3968 Rh [2201-2218] 3'UI

358 GUUUGUUUUUGACAUCAG 2934 CUGAUGUCAAAAACAAAC 3969 [2854-2871] 3'UI

359 UGCACAGCUUUGCUUUAU 2935 AUAAAGCAAAGCUGUGCA 3970 [1862-1879] 3'UI

360 CCUAUUUUCAUCCUGCAA 2936 UUGCAGGAUGAAAAUAGG 3971 [3332-3349] 3'UI

361 UGCCAUUGCUUCUUGCCU 2937 AGGCAAGAAGCAAUGGCA 3972 [1816-1833] 3'UI

362 ACCAACUUCUGCUUGUAU 2938 AUACAAGCAGAAGUUGGU 3973 Rh [2206-2223] 3'UI

363 GGUCCUGUCCUGAGGCUG 2939 CAGCCUCAGGACAGGACC 3974 Rh [1747-1764] 3'UI

364 AUGCAGAUGUAGUGAUCA 2940 UGAUCACUACAUCUGCAU 3975 [420-437] ORF

365 GCUAAGCAUAGUAAGAAG 2941 CUUCUUACUAUGCUUAGC 3976 [2033-2050] 3'UI

366 GUUCCCUCCCUCAAAGAC 2942 GUCUUUGAGGGAGGGAAC 3977 [1972-1989] 3'UI

367 AGCUGUAAUCAUUCCUGU 2943 ACAGGAAUGAUUACAGCU 3978 [2870-2887] 3'UI

368 GCAUGUGACGCCAGCUAA 2944 UUAGCUGGCGUCACAUGC 3979 [2020-2037] 3'UI

369 GCACAGCUUUGCUUUAUC 2945 GAUAAAGCAAAGCUGUGC 3980 [1863-1880] 3'UI

370 GAGCCUCCCUCUGAGCCU 2946 AGGCUCAGAGGGAGGCUC 3981 Rh [1598-1615] 3'UI

371 GGCACCAGGCCAAGUUCU 2947 AGAACUUGGCCUGGUGCC 3982 Rh,Rb,Rt,Ms [855-872] ORF

372 CAGCACAGAUCUUGAUGA 2948 UCAUCAAGAUCUGUGCUG 3983 Rh [2589-2606] 3'UI

373 UGUUCUAAGCACAGCUCU 2949 AGAGCUGUGCUUAGAACA 3984 [3309-3326] 3'UI

374 UGAGCAGAAAACAAAACA 2950 UGUUUUGUUUUCUGCUCA 3985 [3168-3185] 3'UI

375 GGGAACACACAAGAGUUG 2951 CAACUCUUGUGUGUUCCC 3986 [3538-3555] 3'UI

376 CCCUCAAAGACUGACAGC 2952 GCUGUCAGUCUUUGAGGG 3987 Rh [1979-1996] 3'UI

377 CCUUGUUUUCUGCAGCUU 2953 AAGCUGCAGAAAACAAGG 3988 Rh [1417-1434] 3'UI

378 CUGGAAACGACAUUUAUG 2954 CAUAAAUGUCGUUUCCAG 3989 [471-488] ORF

379 GCAAGAUGCACAUCACCC 2955 GGGUGAUGUGCAUCUUGC 3990 Rh,Dg [660-677] ORF

380 UCAGAAUUCCAGUGGGAG 2956 CUCCCACUGGAAUUCUGA 3991 Rh [1583-1600] 3'UI

381 UGUUGAUUUUGUUUCCGU 2957 ACGGAAACAAAAUCAACA 3992 [3453-3470] 3'UI

382 UGCUGGAAUAUGAAGUCU 2958 AGACUUCAUAUUCCAGCA 3993 Ms [3504-3521] 3'UI 383 GUUGUUGAAAGUUGACAA 2959 UUGUCAACUUUCAACAAC 3994 [3552-3569] 3'UI

384 GGUCGUUGCAAGACUGUG 2960 CACAGUCUUGCAACGACC 3995 [1356-1373] 3'UI

385 GUAGGUAUUAGACUUGCA 2961 UGCAAGUCUAAUACCUAC 3996 [2910-2927] 3'UI

386 CUUUGUAUCAUUCUUGAG 2962 CUCAAGAAUGAUACAAAG 3997 [3593-3610] 3'UI

387 GGGAGCACUGUGUUUAUG 2963 CAUAAACACAGUGCUCCC 3998 [3488-3505] 3'UI

388 UGUCUCUGAUGCUUUGUA 2964 UACAAAGCAUCAGAGACA 3999 [3582-3599] 3'UI

389 GUUCCAGCCUCAGCUGAG 2965 CUCAGCUGAGGCUGGAAC 4000 [1652-1669] 3'UI

390 GGUUAGGAUAGGAAGAAC 2966 GUUCUUCCUAUCCUAACC 4001 [2322-2339] 3'UI

391 AUAUACAACUCCACCAGA 2967 UCUGGUGGAGUUGUAUAU 4002 R [2733-2750] 3'UI

392 UCUGAGCCUUGUAGAAAU 2968 AUUUCUACAAGGCUCAGA 4003 R [1607-1624] 3'UI

393 GUGAGGUCCUGUCCUGAG 2969 CUCAGGACAGGACCUCAC 4004 Rh [1743-1760] 3'UI

394 GGGUGGCAGCUGACAGAG 2970 CUCUGUCAGCUGCCACCC 4005 [3200-3217] 3'UI

395 CAAGCAGACUGCGCAUGU 2971 ACAUGCGCAGUCUGCUUG 4006 [3567-3584] 3'UI

396 CUCCCUCUGAGCCUUGUA 2972 UACAAGGCUCAGAGGGAG 4007 Rh [1602-1619] 3'UI

397 GGAGGUAGGUGGCUUUGG 2973 CCAAAGCCACCUACCUCC 4008 Rh [2076-2093] 3'UI

398 GAGCAGAAAACAAAACAG 2974 CUGUUUUGUUUUCUGCUC 4009 [3169-3186] 3'UI

399 AGAAGGCUCUCCAUUUGG 2975 CCAAAUGGAGAGCCUUCU 4010 [3270-3287] 3'UI

400 UAUGAAGUCUGAGACCUU 2976 AAGGUCUCAGACUUCAUA 4011 [3512-3529] 3'UI

401 AACAUUUACUCCUGUUUC 2977 GAAACAGGAGUAAAUGUU 4012 Rh [2811-2828] 3'UI

402 GACGAGUGCCUCUGGAUG 2978 CAUCCAGAGGCACUCGUC 4013 Rh,Rb,Cw [809-826] ORF

403 CUGGGUCACAGAGAAGAA 2979 UUCUUCUCUGUGACCCAG 4014 Rh [829-846] ORF

404 CUAGGAAGGGAAGGAUUU 2980 AAAUCCUUCCCUUCCUAG 4015 Rh [2057-2074] 3'UI

405 CGGCUUCCCUCCCAGUCC 2981 GGACUGGGAGGGAAGCCG 4016 [1236-1253] 3'UI

406 CCAGUGGGAGCCUCCCUC 2982 GAGGGAGGCUCCCACUGG 4017 Rh [1591-1608] 3'UI

407 GAGUUUCUCGACAUCGAG 2983 CUCGAUGUCGAGAAACUC 4018 Ck,Dg [938-955] ORF

408 AGAAGAGCCGGGUGGCAG 2984 CUGCCACCCGGCUCUUCU 4019 [3191-3208] 3'UI

409 ACAUCAGCUGUAAUCAUU 2985 AAUGAUUACAGCUGAUGU 4020 [2865-2882] 3'UI

410 CUCAGAUGAUAGGUGAAC 2986 GUUCACCUAUCAUCUGAG 4021 [2173-2190] 3'UI

411 GCAGGUGGAUUCCUUCAG 2987 CUGAAGGAAUCCACCUGC 4022 Rh [2992-3009] 3'UI

412 GCGCAUGUCUCUGAUGCU 2988 AGCAUCAGAGACAUGCGC 4023 [3577-3594] 3'UI

413 CAGUAUAUACAACUCCAC 2989 GUGGAGUUGUAUAUACUG 4024 Rh [2729-2746] 3'UI

414 CAUUCUUGAGCAAUCGCU 2990 AGCGAUUGCUCAAGAAUG 4025 [3601-3618] 3'UI

415 CCUCCUCGGCAGUGUGUG 2991 CACACACUGCCGAGGAGG 4026 [579-596] ORF

416 UCCUGUUUCUGCUGAUUG 2992 CAAUCAGCAGAAACAGGA 4027 [2820-2837] 3'UI

417 CCCUCCUCGGCAGUGUGU 2993 ACACACUGCCGAGGAGGG 4028 [578-595] ORF

418 UACCCUUGGUAGGUAUUA 2994 UAAUACCUACCAAGGGUA 4029 [2902-2919] 3'UI

419 GCUUCCUGUAUGGUGAUA 2995 UAUCACCAUACAGGAAGC 4030 [2785-2802] 3'UI

420 GGACAUGGCCCUUGUUUU 2996 AAAACAAGGGCCAUGUCC 4031 [1408-1425] 3'UI

421 GCAUGAAUAAAACACUCA 2997 UGAGUGUUUUAUUCAUGC 4032 Rh [1053-1070] 3'UI

422 CCUGUUUCUGCUGAUUGU 2998 ACAAUCAGCAGAAACAGG 4033 [2821-2838] 3'UI

423 GCACAUCACCCUCUGUGA 2999 UCACAGAGGGUGAUGUGC 4034 Rh [667-684] ORF

424 GCCGCUCAAAUACCUUCA 3000 UGAAGGUAUUUGAGCGGC 4035 [3221-3238] 3'UI

425 GCAACAGGCGUUUUGCAA 3001 UUGCAAAACGCCUGUUGC 4036 Cw,Rt,Ms [403-420] ORF

426 GGGACGGCAAGAUGCACA 3002 UGUGCAUCUUGCCGUCCC 4037 [654-671] ORF

427 GCCAGGCACUAUGUGUCU 3003 AGACACAUAGUGCCUGGC 4038 [1179-1196] 3'UI

428 GACACACUCACUUCUUUC 3004 GAAAGAAGUGAGUGUGUC 4039 [2095-2112] 3'UI

429 CUGAGACCUUCCGGUGCU 3005 AGCACCGGAAGGUCUCAG 4040 [3520-3537] 3'UI

430 CAGAAGAAGAGCCUGAAC 3006 GUUCAGGCUCUUCUUCUG 4041 Rh,Rb,Cw,Ms,Pg [719-736] ORF 431 GAUAGGUGAACCUGAGUU 3007 AACUCAGGUUCACCUAUC 4042 [2180-2197] 3'UI

432 GUUCUAUUCAGCGGCAAC 3008 GUUGCCGCUGAAUAGAAC 4043 [2503-2520] 3'UI

433 AGACUGGGAGGGUAUCCA 3009 UGGAUACCCUCCCAGUCU 4044 R [2623-2640] 3'UI

434 GGCCAACUGCAAAAAAAG 3010 CUUUUUUUGCAGUUGGCC 4045 [986-1003] 3'UTI

435 UGGCCUUUAUAUUUGAUC 3011 GAUCAAAUAUAAAGGCCA 4046 [3124-3141] 3'UI

436 GCUGGGAACACACAAGAG 3012 CUCUUGUGUGUUCCCAGC 4047 [3535-3552] 3'UI

437 GUGGAAGCAUUUGACCCA 3013 UGGGUCAAAUGCUUCCAC 4048 [2954-2971] 3'UI

438 CCAUGAUCCCGUGCUACA 3014 UGUAGCACGGGAUCAUGG 4049 Rh,Rb [780-797] ORF

439 CAGGCAGCACUUAGGGAU 3015 AUCCCUAAGUGCUGCCUG 4050 Rh [1282-1299] 3'UI

440 GCAAAGUAAAGGAUCUUU 3016 AAAGAUCCUUUACUUUGC 4051 [3083-3100] 3'UI

441 GUGGACAAUAAACAGUAU 3017 AUACUGUUUAUUGUCCAC 4052 [3625-3642] 3'UI

442 UGCAAAAAAAGCCUCCAA 3018 UUGGAGGCUUUUUUUGCA 4053 [993-1010] 3'UTI

443 CAAGCAGGAGUUUCUCGA 3019 UCGAGAAACUCCUGCUUG 4054 Ck,Dg [931-948] ORF

444 CGUUCCAGCCUCAGCUGA 3020 UCAGCUGAGGCUGGAACG 4055 [1651-1668] 3'UI

445 CGGUCCGUGGACAAUAAA 3021 UUUAUUGUCCACGGACCG 4056 [3619-3636] 3'UI

446 UAGGAUAGGAAGAACUUU 3022 AAAGUUCUUCCUAUCCUA 4057 [2325-2342] 3'UI

447 AGCUGAGUCUUUUUGGUC 3023 GACCAAAAAGACUCAGCU 4058 Rh [1663-1680] 3'UI

448 UGGCUUUGGUGACACACU 3024 AGUGUGUCACCAAAGCCA 4059 [2085-2102] 3'UI

449 GCCGGUGGCUGCCCUCAA 3025 UUGAGGGCAGCCACCGGC 4060 Rh [1774-1791] 3'UI

450 CCUGGAACCAGUGGCUAG 3026 CUAGCCACUGGUUCCAGG 4061 [1532-1549] 3'UI

451 GCCUGUUCUGGCAUCAGG 3027 CCUGAUGCCAGAACAGGC 4062 [1830-1847] 3'UI

452 GACAGAAAAAGCUGGGUC 3028 GACCCAGCUUUUUCUGUC 4063 Rh [1930-1947] 3'UI

453 CAGCCUCCAGGACACUAU 3029 AUAGUGUCCUGGAGGCUG 4064 [2114-2131] 3'UI

454 GAAGCAUUUGACCCAGAG 3030 CUCUGGGUCAAAUGCUUC 4065 [2957-2974] 3'UI

455 GGCAUCAGGCACCUGGAU 3031 AUCCAGGUGCCUGAUGCC 4066 [1839-1856] 3'UI

456 AGGAUAGGAAGAACUUUC 3032 GAAAGUUCUUCCUAUCCU 4067 [2326-2343] 3'UI

457 AGUGCAAGAUCACGCGCU 3033 AGCGCGUGAUCUUGCACU 4068 Dg,Pg [759-776] ORF

458 CUUCGAUCCUUGGGUGCA 3034 UGCACCCAAGGAUCGAAG 4069 Rh [1201-1218] 3'UI

459 GUAAAGGAUCUUUGAGUA 3035 UACUCAAAGAUCCUUUAC 4070 [3088-3105] 3'UI

460 CAGGCACCUGGAUUGAGU 3036 ACUCAAUCCAGGUGCCUG 4071 Rh [1844-1861] 3'UI

461 AUAAGGAGAAUCUCUUGU 3037 ACAAGAGAUUCUCCUUAU 4072 [2353-2370] 3'UI

462 UUCCCUCCCUCAAAGACU 3038 AGUCUUUGAGGGAGGGAA 4073 [1973-1990] 3'UI

463 UCUGGAAACGACAUUUAU 3039 AUAAAUGUCGUUUCCAGA 4074 [470-487] ORF

464 GUAAGAAGUCCAGCCUAG 3040 CUAGGCUGGACUUCUUAC 4075 Rh [2043-2060] 3'UI

465 CAAAACAGGUUAAGAAGA 3041 UCUUCUUAACCUGUUUUG 4076 [3179-3196] 3'UI

466 GGUUGCCAUUGCUUCUUG 3042 CAAGAAGCAAUGGCAACC 4077 Rh [1813-1830] 3'UI

467 AGGUCCUCAUCCCAUCCU 3043 AGGAUGGGAUGAGGACCU 4078 Rh [1155-1172] 3'UI

468 GUCCGUGGACAAUAAACA 3044 UGUUUAUUGUCCACGGAC 4079 [3621-3638] 3'UI

469 UGUGUUUAUGCUGGAAUA 3045 UAUUCCAGCAUAAACACA 4080 [3496-3513] 3'UI

470 GGGCGUUUUCAUGCUGUA 3046 UACAGCAUGAAAACGCCC 4081 Rh [2661-2678] 3'UI

471 GGCACCUGGAUUGAGUUG 3047 CAACUCAAUCCAGGUGCC 4082 [1846-1863] 3'UI

472 CUGUAAUCAUUCCUGUGC 3048 GCACAGGAAUGAUUACAG 4083 Rh [2872-2889] 3'UI

473 GGCCUGGAAAUGUGCAUU 3049 AAUGCACAUUUCCAGGCC 4084 Rh [1321-1338] 3'UI

474 GGGUCGUUGCAAGACUGU 3050 ACAGUCUUGCAACGACCC 4085 [1355-1372] 3'UI

475 CAGGCGUUUUGCAAUGCA 3051 UGCAUUGCAAAACGCCUG 4086 Cw,Rt,Ms [407-424] ORF

476 AGGGUAUCCAGGAAUCGG 3052 CCGAUUCCUGGAUACCCU 4087 [2631-2648] 3'UI

477 CUGGAAAUGUGCAUUUUG 3053 CAAAAUGCACAUUUCCAG 4088 Rh [1324-1341] 3'UI

478 GGUGGCUGCCCUCAAGGU 3054 ACCUUGAGGGCAGCCACC 4089 Rh [1777-1794] 3'UI 479 GGUCCAGCUCUGACAUCC 3055 GGAUGUCAGAGCUGGACC 4090 h [1022-1039] 3'UI

480 GCGGCCUGGGCGUGGUCU 3056 AGACCACGCCCAGGCCGC 4091 [2455-2472] 3'UI

481 UGCAUUUUGCAGAAACUU 3057 AAGUUUCUGCAAAAUGCA 4092 R [1333-1350] 3'UI

482 GUCUUUUAACCGUGCUGA 3058 UCAGCACGGUUAAAAGAC 4093 [3153-3170] 3'UI

483 CUCAAGGUCCCUUCCCUA 3059 UAGGGAAGGGACCUUGAG 4094 [1787-1804] 3'UI

484 AUCCAGUAUGAGAUCAAG 3060 CUUGAUCUCAUACUGGAU 4095 Rh,Rb [506-523] ORF

485 GUCUGAAAGGUGUGGCCU 3061 AGGCCACACCUUUCAGAC 4096 [3112-3129] 3'UI

486 GACGUUGGAGGAAAGAAG 3062 CUUCUUUCCUCCAACGUC 4097 Rt,Ms [608-625] ORF

487 CUUGUUUCCUCCCACCUG 3063 CAGGUGGGAGGAAACAAG 4098 [2366-2383] 3'UI

488 GACCUGGUCAGCACAGAU 3064 AUCUGUGCUGACCAGGUC 4099 Rh [2581-2598] 3'UI

489 GUUGCAGAUAUACCAACU 3065 AGUUGGUAUAUCUGCAAC 4100 Rh [2195-2212] 3'UI

490 CCACACACGUUGGUCUUU 3066 AAAGACCAACGUGUGUGG 4101 [3141-3158] 3'UI

491 CCCUCUGUGACUUCAUCG 3067 CGAUGAAGUCACAGAGGG 4102 Rh,Cw [675-692] ORF

492 GAUCCUUGGGUGCAGGCA 3068 UGCCUGCACCCAAGGAUC 4103 Rh [1205-1222] 3'UI

493 CAAUGAAACCGAAGCUUG 3069 CAAGCUUCGGUUUCAUUG 4104 [2437-2454] 3'UI

494 AGCCUUGUAGAAAUGGGA 3070 UCCCAUUUCUACAAGGCU 4105 Rh [1611-1628] 3'UI

495 CUGUUCGCUUCCUGUAUG 3071 CAUACAGGAAGCGAACAG 4106 [2779-2796] 3'UI

496 AUGUGUUCCCUCAGUGUG 3072 CACACUGAGGGAACACAU 4107 [2280-2297] 3'UI

497 CCAAGCAGGCAGCACUUA 3073 UAAGUGCUGCCUGCUUGG 4108 [1277-1294] 3'UI

498 GCGAGUGCAAGAUCACGC 3074 GCGUGAUCUUGCACUCGC 4109 [756-773] ORF

499 AUAGUUUAAGAAGGCUCU 3075 AGAGCCUUCUUAAACUAU 4110 [3262-3279] 3'UI

500 CAGACUGCGCAUGUCUCU 3076 AGAGACAUGCGCAGUCUG 4111 [3571-3588] 3'UI

501 CCUGUUUUAAGAGACAUC 3077 GAUGUCUCUUAAAACAGG 4112 Rh [2134-2151] 3'UI

502 UCAGUAUAUACAACUCCA 3078 UGGAGUUGUAUAUACUGA 4113 Rh [2728-2745] 3'UI

503 CGGCAAGAUGCACAUCAC 3079 GUGAUGUGCAUCUUGCCG 4114 Rh,Ck,Dg,Pg [658-675] ORF

504 CAUCAGCUGUAAUCAUUC 3080 GAAUGAUUACAGCUGAUG 4115 [2866-2883] 3'UI

505 GCACCUGUUAAGACUCCU 3081 AGGAGUCUUAACAGGUGC 4116 Rh [2527-2544] 3'UI

506 GUCUGAGACCUUCCGGUG 3082 CACCGGAAGGUCUCAGAC 4117 [3518-3535] 3'UI

507 CUUCUUUCUCAGCCUCCA 3083 UGGAGGCUGAGAAAGAAG 4118 [2105-2122] 3'UI

508 GAUAAGGAGAAUCUCUUG 3084 CAAGAGAUUCUCCUUAUC 4119 [2352-2369] 3'UI

509 AGAUAUACCAACUUCUGC 3085 GCAGAAGUUGGUAUAUCU 4120 Rh [2200-2217] 3'UI

510 CUAUGCAGGUGGAUUCCU 3086 AGGAAUCCACCUGCAUAG 4121 Rh [2988-3005] 3'UI

511 AGGAAGCCGCUCAAAUAC 3087 GUAUUUGAGCGGCUUCCU 4122 [3216-3233] 3'UI

512 CGUGCUACAUCUCCUCCC 3088 GGGAGGAGAUGUAGCACG 4123 Rh [789-806] ORF

513 AAAAAAGGUUUCUGCAUC 3089 GAUGCAGAAACCUUUUUU 4124 [2936-2953] 3'UI

514 GGACACGCGGCUUCCCUC 3090 GAGGGAAGCCGCGUGUCC 4125 [1229-1246] 3'UI

515 UAGAGUUUAUCUACACGG 3091 CCGUGUAGAUAAACUCUA 4126 Dg,Pg [558-575] ORF

516 UCAAAGACUGACAGCCAU 3092 AUGGCUGUCAGUCUUUGA 4127 Rh [1982-1999] 3'UI

517 UGACAUCAGCUGUAAUCA 3093 UGAUUACAGCUGAUGUCA 4128 [2863-2880] 3'UI

518 AGUUGCACAGCUUUGCUU 3094 AAGCAAAGCUGUGCAACU 4129 [1859-1876] 3'UI

519 AGUGGCUAGUUCUUGAAG 3095 CUUCAAGAACUAGCCACU 4130 [1541-1558] 3'UI

520 UGGCAACCCUAUCAAGAG 3096 CUCUUGAUAGGGUUGCCA 4131 [487-504] ORF

521 GUGGCUGCCCUCAAGGUC 3097 GACCUUGAGGGCAGCCAC 4132 Rh [1778-1795] 3'UI

522 GCGUUUUGCAAUGCAGAU 3098 AUCUGCAUUGCAAAACGC 4133 [410-427] ORF

523 GAUCAAGCAGAUAAAGAU 3099 AUCUUUAUCUGCUUGAUC 4134 Cw,Dg,Rt,Ms,Pg [517-534] ORF

524 GCAGGCAGCACUUAGGGA 3100 UCCCUAAGUGCUGCCUGC 4135 Rh [1281-1298] 3'UI

525 CUCCAACCCAUAUAACAC 3101 GUGUUAUAUGGGUUGGAG 4136 [2754-2771] 3'UI

526 GAACUAGGGAACCUAUGU 3102 ACAUAGGUUCCCUAGUUC 4137 Rh [2266-2283] 3'UI

527 GACGAUAUACAGGCACAU 3103 AUGUGCCUGUAUAUCGUC 4138 [2401-2418] 3'UI 528 GAAAUAUUGGACUUGCUG 3104 CAGCAAGUCCAAUAUUUC 4139 [3419-3436] 3'UI

529 GAAGCCGCUCAAAUACCU 3105 AGGUAUUUGAGCGGCUUC 4140 [3218-3235] 3'UI

530 GGCAGCCUGGAACCAGUG 3106 CACUGGUUCCAGGCUGCC 4141 [1527-1544] 3'UI

531 GUCUGGAGGGAGACGUGG 3107 CCACGUCUCCCUCCAGAC 4142 [1132-1149] 3'UI

532 CAUAGUAAGAAGUCCAGC 3108 GCUGGACUUCUUACUAUG 4143 [2039-2056] 3'UI

533 CUCCUGUUUCUGCUGAUU 3109 AAUCAGCAGAAACAGGAG 4144 [2819-2836] 3'UI

534 CAGAAUUCCAGUGGGAGC 3110 GCUCCCACUGGAAUUCUG 4145 R [1584-1601] 3'UI

535 AGCACUGUGUUUAUGCUG 3111 CAGCAUAAACACAGUGCU 4146 [3491-3508] 3'UI

536 GUAACAUUUACUCCUGUU 3112 AACAGGAGUAAAUGUUAC 4147 R [2809-2826] 3'UI

537 UGAGCUGCGUUCCAGCCU 3113 AGGCUGGAACGCAGCUCA 4148 [1644-1661] 3'UI

538 AGGUGGAUUCCUUCAGGU 3114 ACCUGAAGGAAUCCACCU 4149 Rh [2994-3011] 3'UI

539 UUUGUUUCCGUUUGGAUU 3115 AAUCCAAACGGAAACAAA 4150 [3460-3477] 3'UI

540 AAAGGAUCUUUGAGUAGG 3116 CCUACUCAAAGAUCCUUU 4151 [3090-3107] 3'UI

541 GGUCUGGAGGGAGACGUG 3117 CACGUCUCCCUCCAGACC 4152 [1131-1148] 3'UI

542 UGAGAUCAAGCAGAUAAA 3118 UUUAUCUGCUUGAUCUCA 4153 Rh,Cw,Dg,Rt,Ms [514-531] ORF

543 GGAGGGUAUCCAGGAAUC 3119 GAUUCCUGGAUACCCUCC 4154 [2629-2646] 3'UI

544 GAGUUGCACAGCUUUGCU 3120 AGCAAAGCUGUGCAACUC 4155 [1858-1875] 3'UI

545 CCUUCACAAUAAAUAGUG 3121 CACUAUUUAUUGUGAAGG 4156 [3233-3250] 3'UI

546 CUUGUUUUCUGCAGCUUC 3122 GAAGCUGCAGAAAACAAG 4157 Rh [1418-1435] 3'UI

547 AUUGAGUUGCACAGCUUU 3123 AAAGCUGUGCAACUCAAU 4158 [1855-1872] 3'UI

548 UGAUUUUGUUUCCGUUUG 3124 CAAACGGAAACAAAAUCA 4159 [3456-3473] 3'UI

549 CAGCUCUCUUCUCCUAUU 3125 AAUAGGAGAAGAGAGCUG 4160 [3320-3337] 3'UI

550 GGCCUACCAGGUCCCUUU 3126 AAAGGGACCUGGUAGGCC 4161 Rh [1379-1396] 3'UI

551 UGUUAUGUUCUAAGCACA 3127 UGUGCUUAGAACAUAACA 4162 [3304-3321] 3'UI

552 GAGCCGGGUGGCAGCUGA 3128 UCAGCUGCCACCCGGCUC 4163 [3195-3212] 3'UI

553 GGAGGAAUCGGUGAGGUC 3129 GACCUCACCGAUUCCUCC 4164 [1733-1750] 3'UI

554 CCUGGGACACCCUGAGCA 3130 UGCUCAGGGUGUCCCAGG 4165 Rh,Dg,Pg [696-713] ORF

555 UGUGCAUUUUGCAGAAAC 3131 GUUUCUGCAAAAUGCACA 4166 Rh,Rt,Ms [1331-1348] 3'UI

556 CCCUCUGCCAGGCACUAU 3132 AUAGUGCCUGGCAGAGGG 4167 [1173-1190] 3'UI

557 AGUCUGAGACCUUCCGGU 3133 ACCGGAAGGUCUCAGACU 4168 [3517-3534] 3'UI

558 CAACUUCUGCUUGUAUUU 3134 AAAUACAAGCAGAAGUUG 4169 Rh [2208-2225] 3'UI

559 CAGCCUGGAACCAGUGGC 3135 GCCACUGGUUCCAGGCUG 4170 [1529-1546] 3'UI

560 GCUUUGGUGACACACUCA 3136 UGAGUGUGUCACCAAAGC 4171 [2087-2104] 3'UI

561 CGCCUGCAUCAAGAGAAG 3137 CUUCUCUUGAUGCAGGCG 4172 Rh,Cw,Dg,Rt,Ms [874-891] ORF

562 CUCCAAGGGUUUCGACUG 3138 CAGUCGAAACCCUUGGAG 4173 Rh [1005-1022] 3'UI

563 UGCUGGGAACACACAAGA 3139 UCUUGUGUGUUCCCAGCA 4174 [3534-3551] 3'UI

564 ACAUUUACUCCUGUUUCU 3140 AGAAACAGGAGUAAAUGU 4175 Rh [2812-2829] 3'UI

565 GGUUUCGACUGGUCCAGC 3141 GCUGGACCAGUCGAAACC 4176 Rh [1012-1029] 3'UI

566 CAGCUGUAAUCAUUCCUG 3142 CAGGAAUGAUUACAGCUG 4177 [2869-2886] 3'UI

567 CCAUCUGCACAUCCUGAG 3143 CUCAGGAUGUGCAGAUGG 4178 Rh [1912-1929] 3'UI

568 CAUCCCAUGGGUCCAAAU 3144 AUUUGGACCCAUGGGAUG 4179 [1069-1086] 3'UI

569 CUGUUUCUGCUGAUUGUU 3145 AACAAUCAGCAGAAACAG 4180 [2822-2839] 3'UI

570 GUGGCUUUGGUGACACAC 3146 GUGUGUCACCAAAGCCAC 4181 [2084-2101] 3'UI

571 GGCAGCUGACAGAGGAAG 3147 CUUCCUCUGUCAGCUGCC 4182 [3204-3221] 3'UI

572 AGAUCUUGAUGACUUCCC 3148 GGGAAGUCAUCAAGAUCU 4183 Rh [2595-2612] 3'UI

573 UGCAAGACUGUGUAGCAG 3149 CUGCUACACAGUCUUGCA 4184 Rh [1362-1379] 3'UI

574 CAGAUGUAGUGAUCAGGG 3150 CCCUGAUCACUACAUCUG 4185 [423-440] ORF

575 CAUUUGGCAUCGUUUAAU 3151 AUUAAACGAUGCCAAAUG 4186 [3281-3298] 3'UI 576 CAGAAAAAGCUGGGUCUU 3152 AAGACCCAGCUUUUUCUG 4187 R [1932-1949] 3'UI

577 CCCAGAGUGGAACGCGUG 3153 CACGCGUUCCACUCUGGG 4188 [2968-2985] 3'UI

578 ACCUGUUAAGACUCCUGA 3154 UCAGGAGUCUUAACAGGU 4189 R [2529-2546] 3'UI

579 CAUCACCCUCUGUGACUU 3155 AAGUCACAGAGGGUGAUG 4190 R ,Cw [670-687] ORF

580 GGCUUCGAUCCUUGGGUG 3156 CACCCAAGGAUCGAAGCC 4191 Rh [1199-1216] 3'UI

581 CCUUGGCACCGUCACAGA 3157 UCUGUGACGGUGCCAAGG 4192 Rh [1257-1274] 3'UI

582 CAAGAGAAGUGACGGCUC 3158 GAGCCGUCACUUCUCUUG 4193 [883-900] ORF

583 AGCUCUCUUCUCCUAUUU 3159 AAAUAGGAGAAGAGAGCU 4194 [3321-3338] 3'UI

584 GCAGCCUGGAACCAGUGG 3160 CCACUGGUUCCAGGCUGC 4195 [1528-1545] 3'UI

585 UGGACUCUGGAAACGACA 3161 UGUCGUUUCCAGAGUCCA 4196 Rh [465-482] ORF

586 CACUCACUUCUUUCUCAG 3162 CUGAGAAAGAAGUGAGUG 4197 [2099-2116] 3'UI

587 ACCGUGCUGAGCAGAAAA 3163 UUUUCUGCUCAGCACGGU 4198 [3161-3178] 3'UI

588 AGAAUCUCUUGUUUCCUC 3164 GAGGAAACAAGAGAUUCU 4199 [2359-2376] 3'UI

589 ACAGCUCUCUUCUCCUAU 3165 AUAGGAGAAGAGAGCUGU 4200 [3319-3336] 3'UI

590 UCCUCAGAAUUCCAGUGG 3166 CCACUGGAAUUCUGAGGA 4201 Rh [1580-1597] 3'UI

591 GGCCCUUGUUUUCUGCAG 3167 CUGCAGAAAACAAGGGCC 4202 Rh [1414-1431] 3'UI

592 GUGGGUCUGGAGGGAGAC 3168 GUCUCCCUCCAGACCCAC 4203 Rh [1128-1145] 3'UI

593 AUCUCUUGUUUCCUCCCA 3169 UGGGAGGAAACAAGAGAU 4204 [2362-2379] 3'UI

594 GAACCACAGGUACCAGAU 3170 AUCUGGUACCUGUGGUUC 4205 Rh,Rb,Cw,Rt,Ms,Pg [733-750] ORF

595 GCCUCCAAGGGUUUCGAC 3171 GUCGAAACCCUUGGAGGC 4206 Rh [1003-1020] 3'UI

596 CAGCAUGAAUAAAACACU 3172 AGUGUUUUAUUCAUGCUG 4207 Rh [1051-1068] 3'UI

597 CACCCAGAAGAAGAGCCU 3173 AGGCUCUUCUUCUGGGUG 4208 Rh,Ck,Cw,Rt,Ms,Pg [715-732] ORF

598 UCAUAAUGGACCAGUCCA 3174 UGGACUGGUCCAUUAUGA 4209 Rh [2703-2720] 3'UI

599 ACAUCACCCUCUGUGACU 3175 AGUCACAGAGGGUGAUGU 4210 Rh [669-686] ORF

600 CCUUCCUGGAAACAGCAU 3176 AUGCUGUUUCCAGGAAGG 4211 Rh,Rb,Rt,Ms [1039-1056] 3'UI

601 AGCCUCCAAGGGUUUCGA 3177 UCGAAACCCUUGGAGGCU 4212 Rh [1002-1019] 3'UI

602 UGACACACUCACUUCUUU 3178 AAAGAAGUGAGUGUGUCA 4213 [2094-2111] 3'UI

603 UGUGGGUCUGGAGGGAGA 3179 UCUCCCUCCAGACCCACA 4214 Rh [1127-1144] 3'UI

604 AGGCUCUCCAUUUGGCAU 3180 AUGCCAAAUGGAGAGCCU 4215 [3273-3290] 3'UI

605 CCAGUCCAUGUGAUUUCA 3181 UGAAAUCACAUGGACUGG 4216 Rh [2713-2730] 3'UI

606 GACGUGGGUCCAAGGUCC 3182 GGACCUUGGACCCACGUC 4217 [1143-1160] 3'UI

607 GGACAGAAAAAGCUGGGU 3183 ACCCAGCUUUUUCUGUCC 4218 Rh [1929-1946] 3'UI

608 CUACCAGGUCCCUUUCAU 3184 AUGAAAGGGACCUGGUAG 4219 Rh [1382-1399] 3'UI

609 AAUCCUCAGAAUUCCAGU 3185 ACUGGAAUUCUGAGGAUU 4220 Rh [1578-1595] 3'UI

610 CUUUGAGUAGGUUCGGUC 3186 GACCGAACCUACUCAAAG 4221 [3097-3114] 3'UI

611 GCCGGGUGGCAGCUGACA 3187 UGUCAGCUGCCACCCGGC 4222 [3197-3214] 3'UI

612 GCAGAAACUUUUGAGGGU 3188 ACCCUCAAAAGUUUCUGC 4223 Rh [1341-1358] 3'UI

613 CAGUGGCUAGUUCUUGAA 3189 UUCAAGAACUAGCCACUG 4224 [1540-1557] 3'UI

614 GAAAUGGGAGCGAGAAAC 3190 GUUUCUCGCUCCCAUUUC 4225 [1620-1637] 3'UI

615 GCAGACUGCGCAUGUCUC 3191 GAGACAUGCGCAGUCUGC 4226 [3570-3587] 3'UI

616 UGUAAUCAUUCCUGUGCU 3192 AGCACAGGAAUGAUUACA 4227 Rh [2873-2890] 3'UI

617 UGGUAGGUAUUAGACUUG 3193 CAAGUCUAAUACCUACCA 4228 [2908-2925] 3'UI

618 CAUUUACUCCUGUUUCUG 3194 CAGAAACAGGAGUAAAUG 4229 Rh [2813-2830] 3'UI

619 AUGAAGUCUGAGACCUUC 3195 GAAGGUCUCAGACUUCAU 4230 [3513-3530] 3'UI

620 CUUGAUGACUUCCCUUUC 3196 GAAAGGGAAGUCAUCAAG 4231 Rh [2599-2616] 3'UI

621 CAACAGGCGUUUUGCAAU 3197 AUUGCAAAACGCCUGUUG 4232 Cw,Rt,Ms [404-421] ORF

622 CCAUAAGCAGGCCUCCAA 3198 UUGGAGGCCUGCUUAUGG 4233 [959-976]

ORF+3'UTR

623 GUACAGUGACCUAAAGUU 3199 AACUUUAGGUCACUGUAC 4234 [2676-2693] 3'UI

624 GCAUAGUAAGAAGUCCAG 3200 CUGGACUUCUUACUAUGC 4235 [2038-2055] 3'UI 625 ACACUCACUUCUUUCUCA 3201 UGAGAAAGAAGUGAGUGU 4236 [2098-2115] 3'UI

626 AUCAAGAGGAUCCAGUAU 3202 AUACUGGAUCCUCUUGAU 4237 R , b [497-514] ORF

627 AGUGAGAAGGAAGUGGAC 3203 GUCCACUUCCUUCUCACU 4238 [452-469] ORF

628 GCCUAUGCAGGUGGAUUC 3204 GAAUCCACCUGCAUAGGC 4239 Rh [2986-3003] 3'UI

629 CACCGUCACAGAUGCCAA 3205 UUGGCAUCUGUGACGGUG 4240 [1263-1280] 3'UI

630 CUUUCUAGGGCAGACUGG 3206 CCAGUCUGCCCUAGAAAG 4241 R [2612-2629] 3'UI

631 CCCUCCCUCAAAGACUGA 3207 UCAGUCUUUGAGGGAGGG 4242 [1975-1992] 3'UI

632 CUAAGCAUAGUAAGAAGU 3208 ACUUCUUACUAUGCUUAG 4243 [2034-2051] 3'UI

633 CAGAUAUACCAACUUCUG 3209 CAGAAGUUGGUAUAUCUG 4244 Rh [2199-2216] 3'UI

634 UUGCAGAUAUACCAACUU 3210 AAGUUGGUAUAUCUGCAA 4245 Rh [2196-2213] 3'UI

635 GCCUCCCUCUGAGCCUUG 3211 CAAGGCUCAGAGGGAGGC 4246 Rh [1600-1617] 3'UI

636 GGAAAUGUGCAUUUUGCA 3212 UGCAAAAUGCACAUUUCC 4247 Rh [1326-1343] 3'UI

637 CUCCCAGGCUUAGUGUUC 3213 GAACACUAAGCCUGGGAG 4248 [1958-1975] 3'UI

638 CUUUGGUGACACACUCAC 3214 GUGAGUGUGUCACCAAAG 4249 [2088-2105] 3'UI

639 CAUCAAGAGAAGUGACGG 3215 CCGUCACUUCUCUUGAUG 4250 [880-897] ORF

640 CAGCCAUCGUUCUGCACG 3216 CGUGCAGAACGAUGGCUG 4251 Rh [1993-2010] 3'UI

641 CAAAGACUGACAGCCAUC 3217 GAUGGCUGUCAGUCUUUG 4252 Rh [1983-2000] 3'UI

642 AGCAGAAAACAAAACAGG 3218 CCUGUUUUGUUUUCUGCU 4253 [3170-3187] 3'UI

643 GCACUUAGGGAUCUCCCA 3219 UGGGAGAUCCCUAAGUGC 4254 Rh [1288-1305] 3'UI

644 UGGACCAGUCCAUGUGAU 3220 AUCACAUGGACUGGUCCA 4255 Rh [2709-2726] 3'UI

645 AUGUGCAUUUUGCAGAAA 3221 UUUCUGCAAAAUGCACAU 4256 Rh,Ms [1330-1347] 3'UI

646 UGUAACAUUUACUCCUGU 3222 ACAGGAGUAAAUGUUACA 4257 Rh [2808-2825] 3'UI

647 GCUGUAAUCAUUCCUGUG 3223 CACAGGAAUGAUUACAGC 4258 Rh [2871-2888] 3'UI

648 UAAGGAGAAUCUCUUGUU 3224 AACAAGAGAUUCUCCUUA 4259 [2354-2371] 3'UI

649 UGACAAGCAGACUGCGCA 3225 UGCGCAGUCUGCUUGUCA 4260 [3564-3581] 3'UI

650 UCCUGUAUGGUGAUAUCA 3226 UGAUAUCACCAUACAGGA 4261 [2788-2805] 3'UI

651 GAUAGGAAGAACUUUCUC 3227 GAGAAAGUUCUUCCUAUC 4262 Rh [2328-2345] 3'UI

652 CAUUCCUGUGCUGUGUUU 3228 AAACACAGCACAGGAAUG 4263 Rh [2879-2896] 3'UI

653 CAAGGUCCCUUCCCUAGC 3229 GCUAGGGAAGGGACCUUG 4264 [1789-1806] 3'UI

654 CCGUCUUUGGUUCUCCAG 3230 CUGGAGAACCAAAGACGG 4265 [3054-3071] 3'UI

655 GCUUCUUGCCUGUUCUGG 3231 CCAGAACAGGCAAGAAGC 4266 [1823-1840] 3'UI

656 UGGGCUGCGAGUGCAAGA 3232 UCUUGCACUCGCAGCCCA 4267 Ck,Rb,Rt [750-767] ORF

657 GAUGGGCUGCGAGUGCAA 3233 UUGCACUCGCAGCCCAUC 4268 Ck,Rb,Rt [748-765] ORF

658 CUGUUCUGGCAUCAGGCA 3234 UGCCUGAUGCCAGAACAG 4269 [1832-1849] 3'UI

659 GGGUAUCCAGGAAUCGGC 3235 GCCGAUUCCUGGAUACCC 4270 [2632-2649] 3'UI

660 GCAACCCUAUCAAGAGGA 3236 UCCUCUUGAUAGGGUUGC 4271 [489-506] ORF

661 CCCAUCUGCACAUCCUGA 3237 UCAGGAUGUGCAGAUGGG 4272 Rh [1911-1928] 3'UI

662 UAUAGUUUAAGAAGGCUC 3238 GAGCCUUCUUAAACUAUA 4273 [3261-3278] 3'UI

663 AGCCUGAACCACAGGUAC 3239 GUACCUGUGGUUCAGGCU 4274 Rh,Rb,Cw,Ms,Pg [728-745] ORF

664 CGUUGCAAGACUGUGUAG 3240 CUACACAGUCUUGCAACG 4275 [1359-1376] 3'UI

665 CGUCACAGAUGCCAAGCA 3241 UGCUUGGCAUCUGUGACG 4276 [1266-1283] 3'UI

666 UGAGAAGGAAGUGGACUC 3242 GAGUCCACUUCCUUCUCA 4277 [454-471] ORF

667 AUCCCUUCCUGGAAACAG 3243 CUGUUUCCAGGAAGGGAU 4278 Rh,Rb,Rt,Ms [1036-1053] 3'UI

668 CAAAGCACCUGUUAAGAC 3244 GUCUUAACAGGUGCUUUG 4279 Rh [2523-2540] 3'UI

669 AGGUCCCUUUCAUCUUGA 3245 UCAAGAUGAAAGGGACCU 4280 Rh [1387-1404] 3'UI

670 CCUUUUAGACAUGGUUGU 3246 ACAACCAUGUCUAAAAGG 4281 [1112-1129] 3'UI

671 AGCCUAGGAAGGGAAGGA 3247 UCCUUCCCUUCCUAGGCU 4282 Rh [2054-2071] 3'UI

672 GCUUUAUCCGGGCUUGUG 3248 CACAAGCCCGGAUAAAGC 4283 [1873-1890] 3'UI

673 CUCUUCUCCUAUUUUCAU 3249 AUGAAAAUAGGAGAAGAG 4284 [3325-3342] 3'UI 674 CGUAAUUUAAAGCUCUGU 3250 ACAGAGCUUUAAAUUACG 4285 [3438-3455] 3'UI

675 CCUAAAGUUGGUAAGAUG 3251 CAUCUUACCAACUUUAGG 4286 R [2685-2702] 3'UI

676 CUGUGCUGUGUUUUUUAU 3252 AUAAAAAACACAGCACAG 4287 R [2884-2901] 3'UI

677 ACCCAGAGUGGAACGCGU 3253 ACGCGUUCCACUCUGGGU 4288 [2967-2984] 3'UI

678 GUUCUAAGCACAGCUCUC 3254 GAGAGCUGUGCUUAGAAC 4289 [3310-3327] 3'UI

679 CUGUGUUUUUUAUUACCC 3255 GGGUAAUAAAAAACACAG 4290 Rh [2889-2906] 3'UI

680 GGACGGCAAGAUGCACAU 3256 AUGUGCAUCUUGCCGUCC 4291 [655-672] ORF

681 GUUGAUUUUGUUUCCGUU 3257 AACGGAAACAAAAUCAAC 4292 [3454-3471] 3'UI

682 CUCCUUUUAGACAUGGUU 3258 AACCAUGUCUAAAAGGAG 4293 [1110-1127] 3'UI

683 UGAUGCUUUGUAUCAUUC 3259 GAAUGAUACAAAGCAUCA 4294 [3588-3605] 3'UI

684 CUUUAUCCGGGCUUGUGU 3260 ACACAAGCCCGGAUAAAG 4295 [1874-1891] 3'UI

685 AUAGAGUUUAUCUACACG 3261 CGUGUAGAUAAACUCUAU 4296 Dg,Pg [557-574] ORF

686 GGGAUCUCCCAGCUGGGU 3262 ACCCAGCUGGGAGAUCCC 4297 [1295-1312] 3'UI

687 GUGAACCUGAGUUGCAGA 3263 UCUGCAACUCAGGUUCAC 4298 Rh [2185-2202] 3'UI

688 AGUGCCUCUGGAUGGACU 3264 AGUCCAUCCAGAGGCACU 4299 Rh,Rb,Cw,Dg,Rt,Ms [813-830] ORF

689 GAAAGUUGACAAGCAGAC 3265 GUCUGCUUGUCAACUUUC 4300 [3558-3575] 3'UI

690 UUGCAAAAUGCUUCCAAA 3266 UUUGGAAGCAUUUUGCAA 4301 Rh [2472-2489] 3'UI

691 GUAAAGAUAAACUGACGA 3267 UCGUCAGUUUAUCUUUAC 4302 Rh [2388-2405] 3'UI

692 CCAAAGCCACCUUAGCCU 3268 AGGCUAAGGUGGCUUUGG 4303 Rh [2485-2502] 3'UI

693 AGAAAAAGCUGGGUCUUG 3269 CAAGACCCAGCUUUUUCU 4304 Rh [1933-1950] 3'UI

694 CUGCCGUAAUUUAAAGCU 3270 AGCUUUAAAUUACGGCAG 4305 [3434-3451] 3'UI

695 UCCCUUUCAUCUUGAGAG 3271 CUCUCAAGAUGAAAGGGA 4306 Rh [1390-1407] 3'UI

696 GAUCUUGAUGACUUCCCU 3272 AGGGAAGUCAUCAAGAUC 4307 Rh [2596-2613] 3'UI

697 UCAGUGUGGUUUCCUGAA 3273 UUCAGGAAACCACACUGA 4308 [2290-2307] 3'UI

698 GGAGCCUCCCUCUGAGCC 3274 GGCUCAGAGGGAGGCUCC 4309 Rh [1597-1614] 3'UI

699 UGGUAAGAUGUCAUAAUG 3275 CAUUAUGACAUCUUACCA 4310 Rh [2693-2710] 3'UI

700 AAGCAUUUGACCCAGAGU 3276 ACUCUGGGUCAAAUGCUU 4311 [2958-2975] 3'UI

701 AGCUAAGAAACUUCCUAG 3277 CUAGGAAGUUUCUUAGCU 4312 [2247-2264] 3'UI

702 CAGGUUAAGAAGAGCCGG 3278 CCGGCUCUUCUUAACCUG 4313 [3184-3201] 3'UI

703 GACUGCGCAUGUCUCUGA 3279 UCAGAGACAUGCGCAGUC 4314 [3573-3590] 3'UI

704 GUAGGUUCGGUCUGAAAG 3280 CUUUCAGACCGAACCUAC 4315 [3103-3120] 3'UI

705 UGAAAGUUGACAAGCAGA 3281 UCUGCUUGUCAACUUUCA 4316 [3557-3574] 3'UI

706 AACUUCUGCUUGUAUUUC 3282 GAAAUACAAGCAGAAGUU 4317 Rh [2209-2226] 3'UI

707 GACAAGCAGACUGCGCAU 3283 AUGCGCAGUCUGCUUGUC 4318 [3565-3582] 3'UI

708 AAGUCUGAGACCUUCCGG 3284 CCGGAAGGUCUCAGACUU 4319 [3516-3533] 3'UI

709 CUCUGACAUCCCUUCCUG 3285 CAGGAAGGGAUGUCAGAG 4320 Rh [1029-1046] 3'UI

710 GUAAACAUACACACGCAA 3286 UUGCGUGUGUAUGUUUAC 4321 Rh [2422-2439] 3'UI

711 CCUCUGGAUGGACUGGGU 3287 ACCCAGUCCAUCCAGAGG 4322 Rh,Rb,Cw,Dg,Rt,Ms, [817-834] ORF

Pg

712 GAUGACUUCCCUUUCUAG 3288 CUAGAAAGGGAAGUCAUC 4323 Rh [2602-2619] 3'UI

713 CCUACCAGGUCCCUUUCA 3289 UGAAAGGGACCUGGUAGG 4324 Rh [1381-1398] 3'UI

714 CAAGGUCCUCAUCCCAUC 3290 GAUGGGAUGAGGACCUUG 4325 [1153-1170] 3'UI

715 GAUCUUUGAGUAGGUUCG 3291 CGAACCUACUCAAAGAUC 4326 [3094-3111] 3'UI

716 AGAAAUAUUGGACUUGCU 3292 AGCAAGUCCAAUAUUUCU 4327 [3418-3435] 3'UI

717 CUGCCCUCAAGGUCCCUU 3293 AAGGGACCUUGAGGGCAG 4328 Rh [1782-1799] 3'UI

718 CUAGGGAACCUAUGUGUU 3294 AACACAUAGGUUCCCUAG 4329 Rh [2269-2286] 3'UI

719 CAAGCAGGCAGCACUUAG 3295 CUAAGUGCUGCCUGCUUG 4330 [1278-1295] 3'UI

720 CCCACCGGGACCUGGUCA 3296 UGACCAGGUCCCGGUGGG 4331 [2573-2590] 3'UI

721 GUUUCUGCAUCGUGGAAG 3297 CUUCCACGAUGCAGAAAC 4332 Rh [2943-2960] 3'UI 722 GUGACCUAAAGUUGGUAA 3298 UUACCAACUUUAGGUCAC 4333 [2681-2698] 3'UI

723 UGGGAACACACAAGAGUU 3299 AACUCUUGUGUGUUCCCA 4334 [3537-3554] 3'UI

724 GAAUCGGUGAGGUCCUGU 3300 ACAGGACCUCACCGAUUC 4335 [1737-1754] 3'UI

725 CCCUCCCAGGCUUAGUGU 3301 ACACUAAGCCUGGGAGGG 4336 [1956-1973] 3'UI

726 CCCACAUCCAAGGGCAGC 3302 GCUGCCCUUGGAUGUGGG 4337 [1515-1532] 3'UI

727 AGCCUCCCUCUGAGCCUU 3303 AAGGCUCAGAGGGAGGCU 4338 R [1599-1616] 3'UI

728 CAUGAUCCCGUGCUACAU 3304 AUGUAGCACGGGAUCAUG 4339 R ,Rb [781-798] ORF

729 CAUAAUGGACCAGUCCAU 3305 AUGGACUGGUCCAUUAUG 4340 Rh [2704-2721] 3'UI

730 GUCACAGAUGCCAAGCAG 3306 CUGCUUGGCAUCUGUGAC 4341 [1267-1284] 3'UI

731 UGCAUCAAGAGAAGUGAC 3307 GUCACUUCUCUUGAUGCA 4342 [878-895] ORF

732 GAGACCUUCCGGUGCUGG 3308 CCAGCACCGGAAGGUCUC 4343 [3522-3539] 3'UI

733 UACCUAGCUAAGAAACUU 3309 AAGUUUCUUAGCUAGGUA 4344 Rh [2242-2259] 3'UI

734 GCUGCGUUCCAGCCUCAG 3310 CUGAGGCUGGAACGCAGC 4345 [1647-1664] 3'UI

735 UGGUUUCCUGAAGCCAGU 3311 ACUGGCUUCAGGAAACCA 4346 [2296-2313] 3'UI

736 GCAGAUGUAGUGAUCAGG 3312 CCUGAUCACUACAUCUGC 4347 [422-439] ORF

737 CACCUGGAUUGAGUUGCA 3313 UGCAACUCAAUCCAGGUG 4348 [1848-1865] 3'UI

738 UUGGUUCUCCAGUUCAAA 3314 UUUGAACUGGAGAACCAA 4349 [3060-3077] 3'UI

739 CUUGGCACCGUCACAGAU 3315 AUCUGUGACGGUGCCAAG 4350 Rh [1258-1275] 3'UI

740 CUUCCAAAGCCACCUUAG 3316 CUAAGGUGGCUUUGGAAG 4351 Rh [2482-2499] 3'UI

741 GGGCCUGGAAAUGUGCAU 3317 AUGCACAUUUCCAGGCCC 4352 Rh [1320-1337] 3'UI

742 CACGCGGCUUCCCUCCCA 3318 UGGGAGGGAAGCCGCGUG 4353 [1232-1249] 3'UI

743 CAAGUUCUUCGCCUGCAU 3319 AUGCAGGCGAAGAACUUG 4354 Rh,Rb,Cw,Dg,Ms [865-882] ORF

744 CUGAAGCCAGUGAUAUGG 3320 CCAUAUCACUGGCUUCAG 4355 [2303-2320] 3'UI

745 UUCUCAGCCUCCAGGACA 3321 UGUCCUGGAGGCUGAGAA 4356 [2110-2127] 3'UI

746 UAUUACCCUUGGUAGGUA 3322 UACCUACCAAGGGUAAUA 4357 [2899-2916] 3'UI

747 AGGAUCUUUGAGUAGGUU 3323 AACCUACUCAAAGAUCCU 4358 [3092-3109] 3'UI

748 GGCUUCCCUCCCAGUCCC 3324 GGGACUGGGAGGGAAGCC 4359 [1237-1254] 3'UI

749 UCUCGGUAAUGAUAAGGA 3325 UCCUUAUCAUUACCGAGA 4360 [2342-2359] 3'UI

750 GCUUGCAGGAGGAAUCGG 3326 CCGAUUCCUCCUGCAAGC 4361 [1726-1743] 3'UI

751 GUGGUCUUGCAAAAUGCU 3327 AGCAUUUUGCAAGACCAC 4362 [2466-2483] 3'UI

752 CCUCAGCUGAGUCUUUUU 3328 AAAAAGACUCAGCUGAGG 4363 Rh [1659-1676] 3'UI

753 AGAAGUGACGGCUCCUGU 3329 ACAGGAGCCGUCACUUCU 4364 [887-904] ORF

754 CGUGGUCUUGCAAAAUGC 3330 GCAUUUUGCAAGACCACG 4365 [2465-2482] 3'UI

755 ACCGGGACCUGGUCAGCA 3331 UGCUGACCAGGUCCCGGU 4366 [2576-2593] 3'UI

756 GAUCCACACACGUUGGUC 3332 GACCAACGUGUGUGGAUC 4367 [3138-3155] 3'UI

757 UAUAUUUGAUCCACACAC 3333 GUGUGUGGAUCAAAUAUA 4368 [3131-3148] 3'UI

758 ACCUAUGUGUUCCCUCAG 3334 CUGAGGGAACACAUAGGU 4369 [2276-2293] 3'UI

759 GUUUUUUAUUACCCUUGG 3335 CCAAGGGUAAUAAAAAAC 4370 Rh [2893-2910] 3'UI

760 GAAGUGGACUCUGGAAAC 3336 GUUUCCAGAGUCCACUUC 4371 [461-478] ORF

761 CGCGGCUUCCCUCCCAGU 3337 ACUGGGAGGGAAGCCGCG 4372 [1234-1251] 3'UI

762 CCCUAUCAAGAGGAUCCA 3338 UGGAUCCUCUUGAUAGGG 4373 [493-510] ORF

763 CCCGGACGAGUGCCUCUG 3339 CAGAGGCACUCGUCCGGG 4374 Rh,Rb,Cw [805-822] ORF

764 CGGUUGCCAUUGCUUCUU 3340 AAGAAGCAAUGGCAACCG 4375 Rh [1812-1829] 3'UI

765 GCUGUGUUUUUUAUUACC 3341 GGUAAUAAAAAACACAGC 4376 Rh [2888-2905] 3'UI

766 CUUCCACGCCUCUGCACU 3342 AGUGCAGAGGCGUGGAAG 4377 [1432-1449] 3'UI

767 GGACCCAUAAGCAGGCCU 3343 AGGCCUGCUUAUGGGUCC 4378 Rh [955-972]

ORF+3'UTR

768 CUGGCAAGUGCUCCCAUC 3344 GAUGGGAGCACUUGCCAG 4379 [1458-1475] 3'UI 769 AAAGGUGUGGCCUUUAUA 3345 UAUAAAGGCCACACCUUU 4380 [3117-3134] 3'UI

770 ACAGGCACAUUAUGUAAA 3346 UUUACAUAAUGUGCCUGU 4381 [2409-2426] 3'UI

771 ACUUCCCUUUCUAGGGCA 3347 UGCCCUAGAAAGGGAAGU 4382 R [2606-2623] 3'UI

772 CUGUUGAUUUUGUUUCCG 3348 CGGAAACAAAAUCAACAG 4383 [3452-3469] 3'UI

773 CAAAGGGCCUGAGAAGGA 3349 UCCUUCUCAGGCCCUUUG 4384 [538-555] ORF

774 CCUGAGCACCACCCAGAA 3350 UUCUGGGUGGUGCUCAGG 4385 Rh,Pg [706-723] ORF

775 UCUUGAUGACUUCCCUUU 3351 AAAGGGAAGUCAUCAAGA 4386 Rh [2598-2615] 3'UI

776 GAGUGCAAGAUCACGCGC 3352 GCGCGUGAUCUUGCACUC 4387 Dg,Pg [758-775] ORF

777 UUGUUUCCGUUUGGAUUU 3353 AAAUCCAAACGGAAACAA 4388 [3461-3478] 3'UI

778 CCUCCCAGUCCCUGCCUU 3354 AAGGCAGGGACUGGGAGG 4389 Rh [1243-1260] 3'UI

779 AGGCCUACCAGGUCCCUU 3355 AAGGGACCUGGUAGGCCU 4390 Rh [1378-1395] 3'UI

780 CAAGAUGCACAUCACCCU 3356 AGGGUGAUGUGCAUCUUG 4391 Rh,Dg [661-678] ORF

781 UGGAGGAAAGAAGGAAUA 3357 UAUUCCUUCUUUCCUCCA 4392 Rt [613-630] ORF

782 UGACAAAGAUUACCUAGC 3358 GCUAGGUAAUCUUUGUCA 4393 [2232-2249] 3'UI

783 GGUGGCUUUGGUGACACA 3359 UGUGUCACCAAAGCCACC 4394 [2083-2100] 3'UI

784 UCACUUCUUUCUCAGCCU 3360 AGGCUGAGAAAGAAGUGA 4395 [2102-2119] 3'UI

785 UAAUCAUUCCUGUGCUGU 3361 ACAGCACAGGAAUGAUUA 4396 Rh [2875-2892] 3'UI

786 AGUAGGUUCGGUCUGAAA 3362 UUUCAGACCGAACCUACU 4397 [3102-3119] 3'UI

787 CGUUUUGCAAUGCAGAUG 3363 CAUCUGCAUUGCAAAACG 4398 [411-428] ORF

788 GGGCACCAGGCCAAGUUC 3364 GAACUUGGCCUGGUGCCC 4399 Rh,Rb,Rt,Ms [854-871] ORF

789 ACAGAGAAGAACAUCAAC 3365 GUUGAUGUUCUUCUCUGU 4400 Rh [836-853] ORF

790 CAAAAAAAGCCUCCAAGG 3366 CCUUGGAGGCUUUUUUUG 4401 [995-1012] 3'UTI

791 UUGGUAGGUAUUAGACUU 3367 AAGUCUAAUACCUACCAA 4402 [2907-2924] 3'UI

792 GAGCACUGUGUUUAUGCU 3368 AGCAUAAACACAGUGCUC 4403 [3490-3507] 3'UI

793 UGUACAGUGACCUAAAGU 3369 ACUUUAGGUCACUGUACA 4404 [2675-2692] 3'UI

794 AAGAAAUAUUGGACUUGC 3370 GCAAGUCCAAUAUUUCUU 4405 [3417-3434] 3'UI

795 CAGAAACUUUUGAGGGUC 3371 GACCCUCAAAAGUUUCUG 4406 Rh [1342-1359] 3'UI

796 UUCCCUUUCUAGGGCAGA 3372 UCUGCCCUAGAAAGGGAA 4407 Rh [2608-2625] 3'UI

797 CACAUCCAAGGGCAGCCU 3373 AGGCUGCCCUUGGAUGUG 4408 [1517-1534] 3'UI

798 CAUCUUGAGAGGGACAUG 3374 CAUGUCCCUCUCAAGAUG 4409 [1397-1414] 3'UI

799 GGCUUUCUGCAUGUGACG 3375 CGUCACAUGCAGAAAGCC 4410 [2012-2029] 3'UI

800 UAGCUAAGAAACUUCCUA 3376 UAGGAAGUUUCUUAGCUA 4411 [2246-2263] 3'UI

801 ACAUCCAAGGGCAGCCUG 3377 CAGGCUGCCCUUGGAUGU 4412 [1518-1535] 3'UI

802 UGUUCCCUCCCUCAAAGA 3378 UCUUUGAGGGAGGGAACA 4413 [1971-1988] 3'UI

803 GUCUUUUUGGUCUGCACC 3379 GGUGCAGACCAAAAAGAC 4414 [1669-1686] 3'UI

804 CCAUGAGCUCCCAGCACC 3380 GGUGCUGGGAGCUCAUGG 4415 [1489-1506] 3'UI

805 AGAUGUAGUGAUCAGGGC 3381 GCCCUGAUCACUACAUCU 4416 [424-441] ORF

806 GAGGUAGGUGGCUUUGGU 3382 ACCAAAGCCACCUACCUC 4417 Rh [2077-2094] 3'UI

807 AAGCCGCUCAAAUACCUU 3383 AAGGUAUUUGAGCGGCUU 4418 [3219-3236] 3'UI

808 UGAGCCUUGUAGAAAUGG 3384 CCAUUUCUACAAGGCUCA 4419 Rh [1609-1626] 3'UI

809 GACGCCAGCUAAGCAUAG 3385 CUAUGCUUAGCUGGCGUC 4420 [2026-2043] 3'UI

810 GCAGCUUCCACGCCUCUG 3386 CAGAGGCGUGGAAGCUGC 4421 Rh [1428-1445] 3'UI

811 AGAAUUCCAGUGGGAGCC 3387 GGCUCCCACUGGAAUUCU 4422 Rh [1585-1602] 3'UI

812 GAACGCGUGGCCUAUGCA 3388 UGCAUAGGCCACGCGUUC 4423 Rh [2977-2994] 3'UI

813 ACAGAAAAAGCUGGGUCU 3389 AGACCCAGCUUUUUCUGU 4424 Rh [1931-1948] 3'UI

814 AAGGAAUAUCUCAUUGCA 3390 UGCAAUGAGAUAUUCCUU 4425 [623-640] ORF

815 CAAGAGGAUCCAGUAUGA 3391 UCAUACUGGAUCCUCUUG 4426 Rh,Rb [499-516] ORF

816 AGCUGACAGAGGAAGCCG 3392 CGGCUUCCUCUGUCAGCU 4427 [3207-3224] 3'UI 817 AUAAAACACUCAUCCCAU 3393 AUGGGAUGAGUGUUUUAU 4428 [1059-1076] 3'UI

818 GAAUCUCUUGUUUCCUCC 3394 GGAGGAAACAAGAGAUUC 4429 [2360-2377] 3'UI

819 GUUAUGUUCUAAGCACAG 3395 CUGUGCUUAGAACAUAAC 4430 [3305-3322] 3'UI

820 ACACGUUGGUCUUUUAAC 3396 GUUAAAAGACCAACGUGU 4431 [3145-3162] 3'UI

821 GGUGCACCCGCAACAGGC 3397 GCCUGUUGCGGGUGCACC 4432 Cw,Dg,Rt,Ms [394-411] ORF

822 UCUGCAUCGUGGAAGCAU 3398 AUGCUUCCACGAUGCAGA 4433 Rh [2946-2963] 3'UI

823 CUGCCAGGCACUAUGUGU 3399 ACACAUAGUGCCUGGCAG 4434 [1177-1194] 3'UI

824 GAAGUCUGAGACCUUCCG 3400 CGGAAGGUCUCAGACUUC 4435 [3515-3532] 3'UI

825 CUGGUCAGCACAGAUCUU 3401 AAGAUCUGUGCUGACCAG 4436 Rh [2584-2601] 3'UI

826 GUGCAUUUUGCAGAAACU 3402 AGUUUCUGCAAAAUGCAC 4437 Rh,Rt,Ms [1332-1349] 3'UI

827 UCAUCUUGAGAGGGACAU 3403 AUGUCCCUCUCAAGAUGA 4438 [1396-1413] 3'UI

828 CACUUAGGGAUCUCCCAG 3404 CUGGGAGAUCCCUAAGUG 4439 Rh [1289-1306] 3'UI

829 CACGCAAUGAAACCGAAG 3405 CUUCGGUUUCAUUGCGUG 4440 [2433-2450] 3'UI

830 GACUGACAGCCAUCGUUC 3406 GAACGAUGGCUGUCAGUC 4441 Rh [1987-2004] 3'UI

831 AUUGCAAAGUAAAGGAUC 3407 GAUCCUUUACUUUGCAAU 4442 [3080-3097] 3'UI

832 AGUGGAACGCGUGGCCUA 3408 UAGGCCACGCGUUCCACU 4443 [2973-2990] 3'UI

833 GUUCGGUCUGAAAGGUGU 3409 ACACCUUUCAGACCGAAC 4444 [3107-3124] 3'UI

834 UGCAGAUGUAGUGAUCAG 3410 CUGAUCACUACAUCUGCA 4445 [421-438] ORF

835 GUGUUCCCUCAGUGUGGU 3411 ACCACACUGAGGGAACAC 4446 [2282-2299] 3'UI

836 UGCCGUAAUUUAAAGCUC 3412 GAGCUUUAAAUUACGGCA 4447 [3435-3452] 3'UI

837 CUGCGGUUGCCAUUGCUU 3413 AAGCAAUGGCAACCGCAG 4448 [1809-1826] 3'UI

838 CGGCUCCUGUGCGUGGUA 3414 UACCACGCACAGGAGCCG 4449 Rh [895-912] ORF

839 GGGUUUCGACUGGUCCAG 3415 CUGGACCAGUCGAAACCC 4450 Rh [1011-1028] 3'UI

840 AGAGAAGAACAUCAACGG 3416 CCGUUGAUGUUCUUCUCU 4451 Rh,Rb,Cw [838-855] ORF

841 AUGGACCAGUCCAUGUGA 3417 UCACAUGGACUGGUCCAU 4452 Rh [2708-2725] 3'UI

842 CCGUGCUACAUCUCCUCC 3418 GGAGGAGAUGUAGCACGG 4453 Rh [788-805] ORF

843 CCAAAGCACCUGUUAAGA 3419 UCUUAACAGGUGCUUUGG 4454 Rh [2522-2539] 3'UI

844 CAACUGCAAAAAAAGCCU 3420 AGGCUUUUUUUGCAGUUG 4455 [989-1006] 3'UTI

845 CUUUCUCAGCCUCCAGGA 3421 UCCUGGAGGCUGAGAAAG 4456 [2108-2125] 3'UI

846 UCUAAAGGUGAAUUCUCA 3422 UGAGAAUUCACCUUUAGA 4457 Ms [2159-2176] 3'UI

847 GCAGACUGGGAGGGUAUC 3423 GAUACCCUCCCAGUCUGC 4458 Rh [2621-2638] 3'UI

848 CUGGAACCAGUGGCUAGU 3424 ACUAGCCACUGGUUCCAG 4459 [1533-1550] 3'UI

849 GACUGUGUAGCAGGCCUA 3425 UAGGCCUGCUACACAGUC 4460 Rh [1367-1384] 3'UI

850 GGCCAAGUUCUUCGCCUG 3426 CAGGCGAAGAACUUGGCC 4461 Rh,Rb,Cw,Dg,Ms [862-879] ORF

851 GUUCGCUUCCUGUAUGGU 3427 ACCAUACAGGAAGCGAAC 4462 [2781-2798] 3'UI

852 AAUUCCAGUGGGAGCCUC 3428 GAGGCUCCCACUGGAAUU 4463 Rh [1587-1604] 3'UI

853 UGCAAAAUGCUUCCAAAG 3429 CUUUGGAAGCAUUUUGCA 4464 Rh [2473-2490] 3'UI

854 CUGGAAUAUGAAGUCUGA 3430 UCAGACUUCAUAUUCCAG 4465 Ms [3506-3523] 3'UI

855 GCUGUGCCCUCCCAGGCU 3431 AGCCUGGGAGGGCACAGC 4466 [1950-1967] 3'UI

856 CCAGAUGGGCUGCGAGUG 3432 CACUCGCAGCCCAUCUGG 4467 Rh,Ck,Rb,Rt [745-762] ORF

857 GCGGUUGCCAUUGCUUCU 3433 AGAAGCAAUGGCAACCGC 4468 [1811-1828] 3'UI

858 AGCUCUGUUGAUUUUGUU 3434 AACAAAAUCAACAGAGCU 4469 [3448-3465] 3'UI

859 UAUCAUUCUUGAGCAAUC 3435 GAUUGCUCAAGAAUGAUA 4470 [3598-3615] 3'UI

860 UGGAGGGAGACGUGGGUC 3436 GACCCACGUCUCCCUCCA 4471 [1135-1152] 3'UI

861 AAGAAACUUCCUAGGGAA 3437 UUCCCUAGGAAGUUUCUU 4472 [2251-2268] 3'UI

862 AAAGCUGGGUCUUGCUGU 3438 ACAGCAAGACCCAGCUUU 4473 Rh [1937-1954] 3'UI

863 AAUAUGAAGUCUGAGACC 3439 GGUCUCAGACUUCAUAUU 4474 [3510-3527] 3'UI

864 UUCCUGAAGCCAGUGAUA 3440 UAUCACUGGCUUCAGGAA 4475 [2300-2317] 3'UI 865 ACUCCUGUUUCUGCUGAU 3441 AUCAGCAGAAACAGGAGU 4476 [2818-2835] 3'UI

866 CCAGGCUUAGUGUUCCCU 3442 AGGGAACACUAAGCCUGG 4477 [1961-1978] 3'UI

867 CCAGAGUGGAACGCGUGG 3443 CCACGCGUUCCACUCUGG 4478 [2969-2986] 3'UI

868 ACCAGGUCCCUUUCAUCU 3444 AGAUGAAAGGGACCUGGU 4479 R [1384-1401] 3'UI

869 CGAGUGCCUCUGGAUGGA 3445 UCCAUCCAGAGGCACUCG 4480 Rh,Rb,Cw,Dg,Rt,Ms [811-828] ORF

870 UAUGUGUUCCCUCAGUGU 3446 ACACUGAGGGAACACAUA 4481 [2279-2296] 3'UI

871 GUUUUCAUGCUGUACAGU 3447 ACUGUACAGCAUGAAAAC 4482 Rh [2665-2682] 3'UI

872 GACUGGGAGGGUAUCCAG 3448 CUGGAUACCCUCCCAGUC 4483 Rh [2624-2641] 3'UI

873 GUCAGCACAGAUCUUGAU 3449 AUCAAGAUCUGUGCUGAC 4484 Rh [2587-2604] 3'UI

874 CGGCCUGGGCGUGGUCUU 3450 AAGACCACGCCCAGGCCG 4485 [2456-2473] 3'UI

875 CUGCGAGUGCAAGAUCAC 3451 GUGAUCUUGCACUCGCAG 4486 Rt [754-771] ORF

876 UGAAAGGUGUGGCCUUUA 3452 UAAAGGCCACACCUUUCA 4487 [3115-3132] 3'UI

877 UGUUCUGGCAUCAGGCAC 3453 GUGCCUGAUGCCAGAACA 4488 [1833-1850] 3'UI

878 GGGCUUGUGUGCAGGGCC 3454 GGCCCUGCACACAAGCCC 4489 Rh [1882-1899] 3'UI

879 CCACCCAGAAGAAGAGCC 3455 GGCUCUUCUUCUGGGUGG 4490 Rh,Ck,Cw,Rt,Ms,Pg [714-731] ORF

880 CAGCUGAGCUGCGUUCCA 3456 UGGAACGCAGCUCAGCUG 4491 [1640-1657] 3'UI

881 UCUGGAUGGACUGGGUCA 3457 UGACCCAGUCCAUCCAGA 4492 Rh,Rb,Cw,Dg,Rt,Ms, [819-836] ORF

Pg

882 CCCAAGCAGGAGUUUCUC 3458 GAGAAACUCCUGCUUGGG 4493 Dg [929-946] ORF

883 AAGGUGUGGCCUUUAUAU 3459 AUAUAAAGGCCACACCUU 4494 [3118-3135] 3'UI

884 CCUCCCAGGCUUAGUGUU 3460 AACACUAAGCCUGGGAGG 4495 [1957-1974] 3'UI

885 CCAACUGCAAAAAAAGCC 3461 GGCUUUUUUUGCAGUUGG 4496 [988-1005] 3'UTI

886 CUGGAUUGAGUUGCACAG 3462 CUGUGCAACUCAAUCCAG 4497 [1851-1868] 3'UI

887 AUGGCCUGUUUUAAGAGA 3463 UCUCUUAAAACAGGCCAU 4498 [2130-2147] 3'UI

888 UGUAUCAUUCUUGAGCAA 3464 UUGCUCAAGAAUGAUACA 4499 [3596-3613] 3'UI

889 AGAGUUUAUCUACACGGC 3465 GCCGUGUAGAUAAACUCU 4500 Dg,Ms,Pg [559-576] ORF

890 CGGGACCUGGUCAGCACA 3466 UGUGCUGACCAGGUCCCG 4501 Rh [2578-2595] 3'UI

891 AUGACAAAGAUUACCUAG 3467 CUAGGUAAUCUUUGUCAU 4502 [2231-2248] 3'UI

892 UGAAGCCAGUGAUAUGGG 3468 CCCAUAUCACUGGCUUCA 4503 [2304-2321] 3'UI

893 GUGGCCUUUAUAUUUGAU 3469 AUCAAAUAUAAAGGCCAC 4504 [3123-3140] 3'UI

894 UAAGCAUAGUAAGAAGUC 3470 GACUUCUUACUAUGCUUA 4505 [2035-2052] 3'UI

895 CUGCACAUCCUGAGGACA 3471 UGUCCUCAGGAUGUGCAG 4506 Rh [1916-1933] 3'UI

896 AGUUGACAAGCAGACUGC 3472 GCAGUCUGCUUGUCAACU 4507 [3561-3578] 3'UI

897 UGAGCUCCCAGCACCUGA 3473 UCAGGUGCUGGGAGCUCA 4508 [1492-1509] 3'UI

898 CUGUUAAGACUCCUGACC 3474 GGUCAGGAGUCUUAACAG 4509 Rh [2531-2548] 3'UI

899 CACAUCACCCUCUGUGAC 3475 GUCACAGAGGGUGAUGUG 4510 Rh [668-685] ORF

900 AAAGUUGACAAGCAGACU 3476 AGUCUGCUUGUCAACUUU 4511 [3559-3576] 3'UI

901 CCAAGUGGCAUGCAGCCC 3477 GGGCUGCAUGCCACUUGG 4512 [2550-2567] 3'UI

902 GUACCAGAUGGGCUGCGA 3478 UCGCAGCCCAUCUGGUAC 4513 Rh,Ck,Rb,Rt [742-759] ORF

903 UGUUUCCGUUUGGAUUUU 3479 AAAAUCCAAACGGAAACA 4514 [3462-3479] 3'UI

904 AUCUUUGAGUAGGUUCGG 3480 CCGAACCUACUCAAAGAU 4515 [3095-3112] 3'UI

905 UGAUCCCGUGCUACAUCU 3481 AGAUGUAGCACGGGAUCA 4516 Rh,Rb [783-800] ORF

906 ACCUGGUCAGCACAGAUC 3482 GAUCUGUGCUGACCAGGU 4517 Rh [2582-2599] 3'UI

907 CACUUCUUUCUCAGCCUC 3483 GAGGCUGAGAAAGAAGUG 4518 [2103-2120] 3'UI

908 GCUGCUGCGGUUGCCAUU 3484 AAUGGCAACCGCAGCAGC 4519 [1805-1822] 3'UI

909 CAUUGCUUCUUGCCUGUU 3485 AACAGGCAAGAAGCAAUG 4520 [1819-1836] 3'UI

910 CUGGAGGGAGACGUGGGU 3486 ACCCACGUCUCCCUCCAG 4521 [1134-1151] 3'UI

911 UGGUGACACACUCACUUC 3487 GAAGUGAGUGUGUCACCA 4522 [2091-2108] 3'UI 912 GGCAGGGCUGGGACACGC 3488 GCGUGUCCCAGCCCUGCC 4523 [1219-1236] 3'UI

913 UGAACCACAGGUACCAGA 3489 UCUGGUACCUGUGGUUCA 4524 Rh,Rb,Cw,Ms,Pg [732-749] ORF

914 GUUAGGAUAGGAAGAACU 3490 AGUUCUUCCUAUCCUAAC 4525 [2323-2340] 3'UI

915 AGCUUUGCUUUAUCCGGG 3491 CCCGGAUAAAGCAAAGCU 4526 [1867-1884] 3'UI

916 CUGUCCUGAGGCUGCUGU 3492 ACAGCAGCCUCAGGACAG 4527 R [1751-1768] 3'UI

917 AUUGCUUCUUGCCUGUUC 3493 GAACAGGCAAGAAGCAAU 4528 [1820-1837] 3'UI

918 GAGCACCACCCAGAAGAA 3494 UUCUUCUGGGUGGUGCUC 4529 Rh,Pg [709-726] ORF

919 GUAGUGAUCAGGGCCAAA 3495 UUUGGCCCUGAUCACUAC 4530 Cw,Rt,Pg [428-445] ORF

920 CCUGUUAAGACUCCUGAC 3496 GUCAGGAGUCUUAACAGG 4531 Rh [2530-2547] 3'UI

921 AGGGUUUCGACUGGUCCA 3497 UGGACCAGUCGAAACCCU 4532 Rh [1010-1027] 3'UI

922 UCAUCCCAUGGGUCCAAA 3498 UUUGGACCCAUGGGAUGA 4533 [1068-1085] 3'UI

923 GCCCUUGUUUUCUGCAGC 3499 GCUGCAGAAAACAAGGGC 4534 Rh [1415-1432] 3'UI

924 GUUGACAAGCAGACUGCG 3500 CGCAGUCUGCUUGUCAAC 4535 [3562-3579] 3'UI

925 AGGGAACCUAUGUGUUCC 3501 GGAACACAUAGGUUCCCU 4536 Rh [2271-2288] 3'UI

926 CCCAGCUGGGUUAGGGCA 3502 UGCCCUAACCCAGCUGGG 4537 [1302-1319] 3'UI

927 GUUGGUCUUUUAACCGUG 3503 CACGGUUAAAAGACCAAC 4538 [3149-3166] 3'UI

928 UUAUGGCAACCCUAUCAA 3504 UUGAUAGGGUUGCCAUAA 4539 [484-501] ORF

929 CUAAAGUUGGUAAGAUGU 3505 ACAUCUUACCAACUUUAG 4540 Rh [2686-2703] 3'UI

930 UGAAUUCUCAGAUGAUAG 3506 CUAUCAUCUGAGAAUUCA 4541 [2167-2184] 3'UI

931 UGCAGGUGGAUUCCUUCA 3507 UGAAGGAAUCCACCUGCA 4542 Rh [2991-3008] 3'UI

932 CUGCGCAUGUCUCUGAUG 3508 CAUCAGAGACAUGCGCAG 4543 [3575-3592] 3'UI

933 GAAGAACAUCAACGGGCA 3509 UGCCCGUUGAUGUUCUUC 4544 Rh,Rb [841-858] ORF

934 GGCGCUCGGCCUCCUGCU 3510 AGCAGGAGGCCGAGCGCC 4545 Dg,Rt,Ms [331-348] ORF

935 CUGAGGACAGAAAAAGCU 3511 AGCUUUUUCUGUCCUCAG 4546 Rh [1925-1942] 3'UI

936 AUCUUGAUGACUUCCCUU 3512 AAGGGAAGUCAUCAAGAU 4547 Rh [2597-2614] 3'UI

937 UAGGUAUUAGACUUGCAC 3513 GUGCAAGUCUAAUACCUA 4548 [2911-2928] 3'UI

938 UGAAGUCUGAGACCUUCC 3514 GGAAGGUCUCAGACUUCA 4549 [3514-3531] 3'UI

939 CCGUAAUUUAAAGCUCUG 3515 CAGAGCUUUAAAUUACGG 4550 [3437-3454] 3'UI

940 AAGGCUCUCCAUUUGGCA 3516 UGCCAAAUGGAGAGCCUU 4551 [3272-3289] 3'UI

941 UAGGGAACCUAUGUGUUC 3517 GAACACAUAGGUUCCCUA 4552 Rh [2270-2287] 3'UI

942 GCUCCCAGCACCUGACUC 3518 GAGUCAGGUGCUGGGAGC 4553 [1495-1512] 3'UI

943 UGGAUUGAGUUGCACAGC 3519 GCUGUGCAACUCAAUCCA 4554 [1852-1869] 3'UI

944 CUGCUGGCGACGCUGCUU 3520 AAGCAGCGUCGCCAGCAG 4555 [347-364] ORF

945 CUGCGUUCCAGCCUCAGC 3521 GCUGAGGCUGGAACGCAG 4556 [1648-1665] 3'UI

946 GUGACUUCAUCGUGCCCU 3522 AGGGCACGAUGAAGUCAC 4557 Rh,Rb,Cw,Dg,Pg [681-698] ORF

947 GCCCUGGGACACCCUGAG 3523 CUCAGGGUGUCCCAGGGC 4558 Rh,Cw,Dg,Pg [694-711] ORF

948 UAUACAACUCCACCAGAC 3524 GUCUGGUGGAGUUGUAUA 4559 Rh [2734-2751] 3'UI

949 ACCUUCCGGUGCUGGGAA 3525 UUCCCAGCACCGGAAGGU 4560 [3525-3542] 3'UI

950 GCUUUCUGCAUGUGACGC 3526 GCGUCACAUGCAGAAAGC 4561 [2013-2030] 3'UI

951 CCACAUCCAAGGGCAGCC 3527 GGCUGCCCUUGGAUGUGG 4562 [1516-1533] 3'UI

952 GCAGCACUUAGGGAUCUC 3528 GAGAUCCCUAAGUGCUGC 4563 Rh [1285-1302] 3'UI

953 UGGGUCCAAGGUCCUCAU 3529 AUGAGGACCUUGGACCCA 4564 [1147-1164] 3'UI

954 UCUAGGGCAGACUGGGAG 3530 CUCCCAGUCUGCCCUAGA 4565 Rh [2615-2632] 3'UI

955 GAAGGGAAGGAUUUUGGA 3531 UCCAAAAUCCUUCCCUUC 4566 Rh [2061-2078] 3'UI

956 GAGGAAUCGGUGAGGUCC 3532 GGACCUCACCGAUUCCUC 4567 [1734-1751] 3'UI

957 AUUUGACCCAGAGUGGAA 3533 UUCCACUCUGGGUCAAAU 4568 [2962-2979] 3'UI

958 GGCGACGCUGCUUCGCCC 3534 GGGCGAAGCAGCGUCGCC 4569 [352-369] ORF

959 UUAGCCUGUUCUAUUCAG 3535 CUGAAUAGAACAGGCUAA 4570 Rh [2496-2513] 3'UI

960 AGCUGAGCUGCGUUCCAG 3536 CUGGAACGCAGCUCAGCU 4571 [1641-1658] 3'UI 961 AAGUUGACAAGCAGACUG 3537 CAGUCUGCUUGUCAACUU 4572 [3560-3577] 3'UI

962 AGCACAGAUCUUGAUGAC 3538 GUCAUCAAGAUCUGUGCU 4573 R [2590-2607] 3'UI

963 GAGGGUAUCCAGGAAUCG 3539 CGAUUCCUGGAUACCCUC 4574 [2630-2647] 3'UI

964 AGUGUGGUUUCCUGAAGC 3540 GCUUCAGGAAACCACACU 4575 [2292-2309] 3'UI

965 UCCUUUUAGACAUGGUUG 3541 CAACCAUGUCUAAAAGGA 4576 [1111-1128] 3'UI

966 GUUUCCUCCCACCUGUGU 3542 ACACAGGUGGGAGGAAAC 4577 [2369-2386] 3'UI

967 CACUAUGGCCUGUUUUAA 3543 UUAAAACAGGCCAUAGUG 4578 [2126-2143] 3'UI

968 CCAGCUGGGUUAGGGCAG 3544 CUGCCCUAACCCAGCUGG 4579 [1303-1320] 3'UI

969 UGCGUUCCAGCCUCAGCU 3545 AGCUGAGGCUGGAACGCA 4580 [1649-1666] 3'UI

970 CCAGCCUAGGAAGGGAAG 3546 CUUCCCUUCCUAGGCUGG 4581 R [2052-2069] 3'UI

971 GCUGGGUCUUGCUGUGCC 3547 GGCACAGCAAGACCCAGC 4582 Rh [1940-1957] 3'UI

972 GUUUCUCGACAUCGAGGA 3548 UCCUCGAUGUCGAGAAAC 4583 Ck,Dg [940-957] ORF

973 GCUGGGACACGCGGCUUC 3549 GAAGCCGCGUGUCCCAGC 4584 [1225-1242] 3'UI

974 UACCAACUUCUGCUUGUA 3550 UACAAGCAGAAGUUGGUA 4585 Rh [2205-2222] 3'UI

975 UCCAAGGGCAGCCUGGAA 3551 UUCCAGGCUGCCCUUGGA 4586 [1521-1538] 3'UI

976 CAACCCUAUCAAGAGGAU 3552 AUCCUCUUGAUAGGGUUG 4587 [490-507] ORF

977 CAGCUGAGUCUUUUUGGU 3553 ACCAAAAAGACUCAGCUG 4588 Rh [1662-1679] 3'UI

978 UGUUAAGACUCCUGACCC 3554 GGGUCAGGAGUCUUAACA 4589 Rh [2532-2549] 3'UI

979 UAUCAAGAGGAUCCAGUA 3555 UACUGGAUCCUCUUGAUA 4590 Rh,Rb [496-513] ORF

980 GCACCAGGCCAAGUUCUU 3556 AAGAACUUGGCCUGGUGC 4591 Rh,Rb,Cw,Rt,Ms [856-873] ORF

981 GGGCUGGGACACGCGGCU 3557 AGCCGCGUGUCCCAGCCC 4592 [1223-1240] 3'UI

982 GGUCCCUUCCCUAGCUGC 3558 GCAGCUAGGGAAGGGACC 4593 [1792-1809] 3'UI

983 UGAUAGGUGAACCUGAGU 3559 ACUCAGGUUCACCUAUCA 4594 [2179-2196] 3'UI

984 AUUCCUGUGCUGUGUUUU 3560 AAAACACAGCACAGGAAU 4595 Rh [2880-2897] 3'UI

985 GAUGCACAUCACCCUCUG 3561 CAGAGGGUGAUGUGCAUC 4596 Rh [664-681] ORF

986 CCAGGCACUAUGUGUCUG 3562 CAGACACAUAGUGCCUGG 4597 [1180-1197] 3'UI

987 GCUGCUGGCGACGCUGCU 3563 AGCAGCGUCGCCAGCAGC 4598 [346-363] ORF

988 UCCAGUGGGAGCCUCCCU 3564 AGGGAGGCUCCCACUGGA 4599 Rh [1590-1607] 3'UI

989 AGCUCUGACAUCCCUUCC 3565 GGAAGGGAUGUCAGAGCU 4600 Rh [1027-1044] 3'UI

990 ACAGCUUUGCUUUAUCCG 3566 CGGAUAAAGCAAAGCUGU 4601 [1865-1882] 3'UI

991 GGGAACCUAUGUGUUCCC 3567 GGGAACACAUAGGUUCCC 4602 Rh [2272-2289] 3'UI

992 CAGGAGUUUCUCGACAUC 3568 GAUGUCGAGAAACUCCUG 4603 Ck,Dg [935-952] ORF

993 GUCCCUUCCCUAGCUGCU 3569 AGCAGCUAGGGAAGGGAC 4604 [1793-1810] 3'UI

994 AGGUUCGGUCUGAAAGGU 3570 ACCUUUCAGACCGAACCU 4605 [3105-3122] 3'UI

995 UGACGAUAUACAGGCACA 3571 UGUGCCUGUAUAUCGUCA 4606 [2400-2417] 3'UI

996 AGUCUUUUUGGUCUGCAC 3572 GUGCAGACCAAAAAGACU 4607 [1668-1685] 3'UI

997 CACCCUGAGCACCACCCA 3573 UGGGUGGUGCUCAGGGUG 4608 Rh,Pg [703-720] ORF

998 GAGAAGAACAUCAACGGG 3574 CCCGUUGAUGUUCUUCUC 4609 Rh,Rb [839-856] ORF

999 GAGAAGUGACGGCUCCUG 3575 CAGGAGCCGUCACUUCUC 4610 [886-903] ORF

1000 UGCGAGUGCAAGAUCACG 3576 CGUGAUCUUGCACUCGCA 4611 [755-772] ORF

1001 AAGUAAAGGAUCUUUGAG 3577 CUCAAAGAUCCUUUACUU 4612 [3086-3103] 3'UI

1002 AGGCACAUUAUGUAAACA 3578 UGUUUACAUAAUGUGCCU 4613 Rh [2411-2428] 3'UI

1003 CGCUCGGUCCGUGGACAA 3579 UUGUCCACGGACCGAGCG 4614 [3615-3632] 3'UI

1004 GUUAAGAAGAGCCGGGUG 3580 CACCCGGCUCUUCUUAAC 4615 [3187-3204] 3'UI

1005 GUGGAACGCGUGGCCUAU 3581 AUAGGCCACGCGUUCCAC 4616 [2974-2991] 3'UI

1006 AAAGUUGGUAAGAUGUCA 3582 UGACAUCUUACCAACUUU 4617 Rh [2688-2705] 3'UI

1007 AGCUGCUGCGGUUGCCAU 3583 AUGGCAACCGCAGCAGCU 4618 [1804-1821] 3'UI

1008 CUGCAUCGUGGAAGCAUU 3584 AAUGCUUCCACGAUGCAG 4619 Rh [2947-2964] 3'UI 1009 UACUCCUGUUUCUGCUGA 3585 UCAGCAGAAACAGGAGUA 4620 [2817-2834] 3'UI

1010 CCUUGUAGAAAUGGGAGC 3586 GCUCCCAUUUCUACAAGG 4621 R [1613-1630] 3'UI

1011 AACCUAUGUGUUCCCUCA 3587 UGAGGGAACACAUAGGUU 4622 [2275-2292] 3'UI

1012 UAGUUUAAGAAGGCUCUC 3588 GAGAGCCUUCUUAAACUA 4623 [3263-3280] 3'UI

1013 UGCGCAUGUCUCUGAUGC 3589 GCAUCAGAGACAUGCGCA 4624 [3576-3593] 3'UI

1014 AGAGAAGUGACGGCUCCU 3590 AGGAGCCGUCACUUCUCU 4625 [885-902] ORF

1015 CAAGGGUUUCGACUGGUC 3591 GACCAGUCGAAACCCUUG 4626 R [1008-1025] 3'UI

1016 UCUAAGCACAGCUCUCUU 3592 AAGAGAGCUGUGCUUAGA 4627 [3312-3329] 3'UI

1017 AUUUGAUCCACACACGUU 3593 AACGUGUGUGGAUCAAAU 4628 [3134-3151] 3'UI

1018 CUUCCCUCCCAGUCCCUG 3594 CAGGGACUGGGAGGGAAG 4629 [1239-1256] 3'UI

1019 AAGAAGGCUCUCCAUUUG 3595 CAAAUGGAGAGCCUUCUU 4630 [3269-3286] 3'UI

1020 CGGGUGGCAGCUGACAGA 3596 UCUGUCAGCUGCCACCCG 4631 [3199-3216] 3'UI

1021 UGGGAGCCUCCCUCUGAG 3597 CUCAGAGGGAGGCUCCCA 4632 Rh [1595-1612] 3'UI

1022 UAUACCAACUUCUGCUUG 3598 CAAGCAGAAGUUGGUAUA 4633 Rh [2203-2220] 3'UI

1023 UGGAUGGACUGGGUCACA 3599 UGUGACCCAGUCCAUCCA 4634 Rh,Rt,Ms,Pg [821-838] ORF

1024 CAGAGUGGAACGCGUGGC 3600 GCCACGCGUUCCACUCUG 4635 [2970-2987] 3'UI

1025 UCUCUUGUUUCCUCCCAC 3601 GUGGGAGGAAACAAGAGA 4636 [2363-2380] 3'UI

1026 CACCAUGAGCUCCCAGCA 3602 UGCUGGGAGCUCAUGGUG 4637 [1487-1504] 3'UI

1027 AUCUGCACAUCCUGAGGA 3603 UCCUCAGGAUGUGCAGAU 4638 Rh [1914-1931] 3'UI

1028 CCCUUGUUUUCUGCAGCU 3604 AGCUGCAGAAAACAAGGG 4639 Rh [1416-1433] 3'UI

1029 CCCUUCCUGGAAACAGCA 3605 UGCUGUUUCCAGGAAGGG 4640 Rh,Rb,Rt,Ms [1038-1055] 3'UI

1030 ACCAUGAGCUCCCAGCAC 3606 GUGCUGGGAGCUCAUGGU 4641 [1488-1505] 3'UI

1031 CACACGUUGGUCUUUUAA 3607 UUAAAAGACCAACGUGUG 4642 [3144-3161] 3'UI

1032 CUGAGUCUUUUUGGUCUG 3608 CAGACCAAAAAGACUCAG 4643 [1665-1682] 3'UI

1033 CCCUCCCAGUCCCUGCCU 3609 AGGCAGGGACUGGGAGGG 4644 Rh [1242-1259] 3'UI

1034 UCAGCCUCCAGGACACUA 3610 UAGUGUCCUGGAGGCUGA 4645 [2113-2130] 3'UI

1035 UGCUUUAUCCGGGCUUGU 3611 ACAAGCCCGGAUAAAGCA 4646 [1872-1889] 3'UI

Table B6: 18 -mer siTIMP2 Cross-Species

17 CACAGGUACCAGAUGGGC 4663 GCCCAUCUGGUACCUGUG 4723 Rh,Rb,Cw,Rt,Ms,Pg [737-754] ORF

18 CCCGCAACAGGCGUUUUG 4664 CAAAACGCCUGUUGCGGG 4724 Cw,Rt,Ms [400-417] ORF

19 UCAAGCAGAUAAAGAUGU 4665 ACAUCUUUAUCUGCUUGA 4725 Cw,Dg,Rt,Ms,Pg [519-536] ORF

20 CACCAGGCCAAGUUCUUC 4666 GAAGAACUUGGCCUGGUG 4726 Rh,Rb,Cw,Ms [857-874] ORF

21 ACCACAGGUACCAGAUGG 4667 CCAUCUGGUACCUGUGGU 4727 Rh,Rb,Cw,Rt,Ms,Pg [735-752] ORF

22 UCUCGCUGGACGUUGGAG 4668 CUCCAACGUCCAGCGAGA 4728 Rt,Ms [600-617] ORF

23 CAAGCAGAUAAAGAUGUU 4669 AACAUCUUUAUCUGCUUG 4729 Cw,Dg,Rt,Ms,Pg [520-537] ORF

24 GAUAAAGAUGUUCAAAGG 4670 CCUUUGAACAUCUUUAUC 4730 Dg,Rt,Ms [526-543] ORF

25 GCACCCGCAACAGGCGUU 4671 AACGCCUGUUGCGGGUGC 4731 Cw,Dg,Rt,Ms [397-414] ORF

26 CAGGCCAAGUUCUUCGCC 4672 GGCGAAGAACUUGGCCUG 4732 Rh,Rb,Cw,Dg,Ms [860-877] ORF

27 UGCACCCGCAACAGGCGU 4673 ACGCCUGUUGCGGGUGCA 4733 Cw,Dg,Rt,Ms [396-413] ORF

28 CAGGUACCAGAUGGGCUG 4674 CAGCCCAUCUGGUACCUG 4734 Rh,Rb,Cw,Dg,Rt,Ms,Pg [739-756] ORF

29 GCUGGCGCUCGGCCUCCU 4675 AGGAGGCCGAGCGCCAGC 4735 Dg,Rt,Ms [328-345] ORF

30 GCGCUCGGCCUCCUGCUG 4676 CAGCAGGAGGCCGAGCGC 4736 Dg,Rt,Ms [332-349] ORF

31 GACGCCUGCAGCUGCUCC 4677 GGAGCAGCUGCAGGCGUC 4737 Cw,Dg,Rt,Ms [374-391] ORF

32 UACCAGAUGGGCUGCGAG 4678 CUCGCAGCCCAUCUGGUA 4738 Rh,Ck,Rb,Rt [743-760] ORF

33 GCUCGGCCUCCUGCUGCU 4679 AGCAGCAGGAGGCCGAGC 4739 Dg,Rt,Ms [334-351] ORF

34 CGGUGCACCCGCAACAGG 4680 CCUGUUGCGGGUGCACCG 4740 Cw,Dg,Rt,Ms [393-410] ORF

35 CCGGUGCACCCGCAACAG 4681 CUGUUGCGGGUGCACCGG 4741 Cw,Dg,Rt,Ms [392-409] ORF

36 ACCCGCAACAGGCGUUUU 4682 AAAACGCCUGUUGCGGGU 4742 Cw,Rt,Ms [399-416] ORF

37 AUCAAGCAGAUAAAGAUG 4683 CAUCUUUAUCUGCUUGAU 4743 Cw,Dg,Rt,Ms,Pg [518-535] ORF

38 CCACAGGUACCAGAUGGG 4684 CCCAUCUGGUACCUGUGG 4744 Rh,Rb,Cw,Rt,Ms,Pg [736-753] ORF

39 CCGACGCCUGCAGCUGCU 4685 AGCAGCUGCAGGCGUCGG 4745 Cw,Dg,Rt,Ms [372-389] ORF

40 CUUCAUCGUGCCCUGGGA 4686 UCCCAGGGCACGAUGAAG 4746 Rh,Rb,Cw,Dg,Pg [685-702] ORF

41 CGGCCGACGCCUGCAGCU 4687 AGCUGCAGGCGUCGGCCG 4747 Cw,Dg,Rt,Ms [369-386] ORF

42 GUGCACCCGCAACAGGCG 4688 CGCCUGUUGCGGGUGCAC 4748 Cw,Dg,Rt,Ms [395-412] ORF

43 CGACGCCUGCAGCUGCUC 4689 GAGCAGCUGCAGGCGUCG 4749 Cw,Dg,Rt,Ms [373-390] ORF

44 ACCAGGCCAAGUUCUUCG 4690 CGAAGAACUUGGCCUGGU 4750 Rh,Rb,Cw,Ms [858-875] ORF

45 UGCCUCUGGAUGGACUGG 4691 CCAGUCCAUCCAGAGGCA 4751 Rh,Rb,Cw,Dg,Rt,Ms [815-832] ORF

46 AACAGGCGUUUUGCAAUG 4692 CAUUGCAAAACGCCUGUU 4752 Cw,Rt,Ms [405-422] ORF

47 CUCGGCCUCCUGCUGCUG 4693 CAGCAGCAGGAGGCCGAG 4753 Dg,Rt [335-352] ORF

48 CGGCCUCCUGCUGCUGGC 4694 GCCAGCAGCAGGAGGCCG 4754 Dg,Rt [337-354] ORF

49 CCAGGCCAAGUUCUUCGC 4695 GCGAAGAACUUGGCCUGG 4755 Rh,Rb,Cw,Dg,Ms [859-876] ORF

50 CUGGCGCUCGGCCUCCUG 4696 CAGGAGGCCGAGCGCCAG 4756 Dg,Rt,Ms [329-346] ORF

51 UCGGCCUCCUGCUGCUGG 4697 CCAGCAGCAGGAGGCCGA 4757 Dg,Rt [336-353] ORF

52 UGGCGCUCGGCCUCCUGC 4698 GCAGGAGGCCGAGCGCCA 4758 Dg,Rt,Ms [330-347] ORF

53 AGGUACCAGAUGGGCUGC 4699 GCAGCCCAUCUGGUACCU 4759 Rh,Ck,Rb,Rt [740-757] ORF

54 CUGUGACUUCAUCGUGCC 4700 GGCACGAUGAAGUCACAG 4760 Rh,Rb,Cw,Dg,Pg [679-696] ORF

55 GACUUCAUCGUGCCCUGG 4701 CCAGGGCACGAUGAAGUC 4761 Rh,Rb,Cw,Dg,Pg [683-700] ORF

56 ACGCCUGCAGCUGCUCCC 4702 GGGAGCAGCUGCAGGCGU 4762 Cw,Dg,Rt,Ms [375-392] ORF

57 AAGAGCCUGAACCACAGG 4703 CCUGUGGUUCAGGCUCUU 4763 Rh,Rb,Cw,Ms,Pg [725-742] ORF

58 CAGGGCCAAAGCGGUCAG 4704 CUGACCGCUUUGGCCCUG 4764 Rb,Dg [436-453] ORF

59 UGACUUCAUCGUGCCCUG 4705 CAGGGCACGAUGAAGUCA 4765 Rh,Rb,Cw,Dg,Pg [682-699] ORF

60 UGUGACUUCAUCGUGCCC 4706 GGGCACGAUGAAGUCACA 4766 Rh,Rb,Cw,Dg,Pg [680-697] ORF

Table B7: Preferred 18+1 -mer siTIMP2 siTIMP2 p3 GGGUCUCGCUGGACGUUGA 4769 UCAACGUCCAGCGAGACCC 4817 18+1 [597-614] O F siTIMP2 p5 GGACUGGGUCACAGAGAAA 4770 UUUCUCUGUGACCCAGUCC 4818 18+1 [826-843] ORF siTIMP2 p6 CUGCAUCAAGAGAAGUGAA 4771 UUCACUUCUCUUGAUGCAG 4819 18+1 [877-894] ORF siTIMP2 p7 GAGGAAAGAAGGAAUAUCA 4772 UGAUAUUCCUUCUUUCCUC 4820 18+1 [615-632] ORF siTIMP2 p8 GCUGGACGUUGGAGGAAAA 4773 UUUUCCUCCAACGUCCAGC 4821 18+1 [604-621] ORF siTIMP2 p9 GGCGUUUUGCAAUGCAGAA 4774 UUCUGCAUUGCAAAACGCC 4822 18+1 [409-426] ORF siTIMP2 plO GCCUGCAUCAAGAGAAGUA 4775 UACUUCUCUUGAUGCAGGC 4823 18+1 [875-892] ORF siTIMP2 pll AGGAAAGAAGGAAUAUCUA 4776 UAGAUAUUCCUUCUUUCCU 4824 18+1 [616-633] ORF siTIMP2 pl2 AGAUCAAGCAGAUAAAGAA 4777 UUCUUUAUCUGCUUGAUCU 4825 18+1 [516-533] ORF siTIMP2 pl3 GUUGGAGGAAAGAAGGAAA 4778 UUUCCUUCUUUCCUCCAAC 4826 18+1 [611-628] ORF siTIMP2 pl4 GCUGCGAGUGCAAGAUCAA 4779 UUGAUCUUGCACUCGCAGC 4827 18+1 [753-770] ORF siTIMP2 pl5 GGGCUGCGAGUGCAAGAUA 4780 UAUCUUGCACUCGCAGCCC 4828 18+1 [751-768] ORF siTIMP2 pl9 GACAUCCCUUCCUGGAAAA 4781 UUUUCCAGGAAGGGAUGUC 4829 18+1 [1033-1050] 3'UTR siTIMP2 p21 GAUGGACUGGGUCACAGAA 4782 UUCUGUGACCCAGUCCAUC 4830 18+1 [823-840] ORF siTIMP2 p22 GCCUCUGGAUGGACUGGGA 4783 UCCCAGUCCAUCCAGAGGC 4831 18+1 [816-833] ORF siTIMP2 _p23 GAGUGCCUCUGGAUGGACA 4784 UGUCCAUCCAGAGGCACUC 4832 18+1 [812-829] ORF siTIMP2 p26 GGCACCAGGCCAAGUUCUA 4785 UAGAACUUGGCCUGGUGCC 4833 18+1 [855-872] ORF siTIMP2 p28 GCAACAGGCGUUUUGCAAA 4786 UUUGCAAAACGCCUGUUGC 4834 18+1 [403-420] ORF siTIMP2 p31 GACGUUGGAGGAAAGAAGA 4787 UCUUCUUUCCUCCAACGUC 4835 18+1 [608-625] ORF siTIMP2 p32 GAUCAAGCAGAUAAAGAUA 4788 UAUCUUUAUCUGCUUGAUC 4836 18+1 [517-534] ORF siTIMP2 p34 UGAGAUCAAGCAGAUAAAA 4789 UUUUAUCUGCUUGAUCUCA 4837 18+1 [514-531] ORF siTIMP2 p36 UGUGCAUUUUGCAGAAACA 4790 UGUUUCUGCAAAAUGCACA 4838 18+1 [1331-1348] 3'UTR siTIMP2 p42 GAACCACAGGUACCAGAUA 4791 UAUCUGGUACCUGUGGUUC 4839 18+1 [733-750] ORF siTIMP2 p43 CACCCAGAAGAAGAGCCUA 4792 UAGGCUCUUCUUCUGGGUG 4840 18+1 [715-732] ORF siTIMP2 p45 CCUUCCUGGAAACAGCAUA 4793 UAUGCUGUUUCCAGGAAGG 4841 18+1 [1039-1056] 3'UTR siTIMP2 p47 UGGGCUGCGAGUGCAAGAA 4794 UUCUUGCACUCGCAGCCCA 4842 18+1 [750-767] ORF siTIMP2 p48 GAUGGGCUGCGAGUGCAAA 4795 UUUGCACUCGCAGCCCAUC 4843 18+1 [748-765] ORF siTIMP2 p49 AUCCCUUCCUGGAAACAGA 4796 UCUGUUUCCAGGAAGGGAU 4844 18+1 [1036-1053] 3TJTR siTIMP2_p50 AGUGCCUCUGGAUGGACUA 4797 UAGUCCAUCCAGAGGCACU 4845 18+1 [813-830] ORF siTIMP2 p52 UGGAGGAAAGAAGGAAUAA 4798 UUAUUCCUUCUUUCCUCCA 4846 18+1 [613-630] ORF siTIMP2 p53 GGGCACCAGGCCAAGUUCA 4799 UGAACUUGGCCUGGUGCCC 4847 18+1 [854-871] ORF siTIMP2 p54 GUGCAUUUUGCAGAAACUA 4800 UAGUUUCUGCAAAAUGCAC 4848 18+1 [1332-1349] 3'UTR siTIMP2 p56 CCAGAUGGGCUGCGAGUGA 4801 UCACUCGCAGCCCAUCUGG 4849 18+1 [745-762] ORF siTIMP2 p57 CGAGUGCCUCUGGAUGGAA 4802 UUCCAUCCAGAGGCACUCG 4850 18+1 [811-828] ORF siTIMP2 p58 CUGCGAGUGCAAGAUCACA 4803 UGUGAUCUUGCACUCGCAG 4851 18+1 [754-771] ORF siTIMP2 p59 UCUGGAUGGACUGGGUCAA 4804 UUGACCCAGUCCAUCCAGA 4852 18+1 [819-836] ORF siTIMP2 p60 GUACCAGAUGGGCUGCGAA 4805 UUCGCAGCCCAUCUGGUAC 4853 18+1 [742-759] ORF siTIMP2 p63 GUAGUGAUCAGGGCCAAAA 4806 UUUUGGCCCUGAUCACUAC 4854 18+1 [428-445] ORF siTIMP2 p66 GGCGCUCGGCCUCCUGCUA 4807 UAGCAGGAGGCCGAGCGCC 4855 18+1 [331-348] ORF siTIMP2 p70 UGGAUGGACUGGGUCACAA 4808 UUGUGACCCAGUCCAUCCA 4856 18+1 [821-838] ORF siTIMP2 p72 CCCUUCCUGGAAACAGCAA 4809 UUGCUGUUUCCAGGAAGGG 4857 18+1 [1038-1055] 3'UTR siTIMP2_p73 ACCAGAUGGGCUGCGAGUA 4810 UACUCGCAGCCCAUCUGGU 4858 18+1 [744-761] ORF siTIMP2 p74 ACAGGUACCAGAUGGGCUA 4811 UAGCCCAUCUGGUACCUGU 4859 18+1 [738-755] ORF siTIMP2 p77 CGGGCACCAGGCCAAGUUA 4812 UAACUUGGCCUGGUGCCCG 4860 18+1 [853-870] ORF siTIMP2 p80 CAUCCCUUCCUGGAAACAA 4813 UUGUUUCCAGGAAGGGAUG 4861 18+1 [1035-1052] 3'UTR siTIMP2 p81 CACCCGCAACAGGCGUUUA 4814 UAAACGCCUGUUGCGGGUG 4862 18+1 [398-415] ORF Table B8: 18+1 -mer siTIMP2 with lowest predicted OT effect

Example 6

In vitro testing of the siRNA compounds for the target genes

[00400] Low- Throughput- Screen (LTS) for siRNA oligos directed to human and rat TIMP1 and TIMP2 gene.

[00401] About 2X10 5 human cell lines (HeLa, LX2, hHSC or PC3) endogenously expressing TIMP1 or TIMP2 gene, are inoculated in 1.5 mL growth medium in order to reach 30-50% confluence after 24 hours. Cells are transfected with Lipofectamine2000® reagent to a final concentration of 0.01-5 nM per transfected cells. Cells aere incubated at 37+FC, 5% C0 2 for 48 hours. siRNA transfected cells are harvested and RNA is isolated using EZ-RNA® kit [Biological Industries (#20-410-100)].

[00402] Reverse transcription is performed as follows: Synthesis of cDNA is performed and human TIMP1 and TIMP2 mRNA levels are determined by Real Time qPCR and normalized to those of the Cyclophilin A (CYNA, PPIA) mRNA for each sample. siRNA activity is determined based on the ratio of the TIMPl or TIMP2 mRNA quantity in siRNA- treated samples versus non-transfected control samples.

[00403] The most active sequences are selected from additional, assays.

IC50 values for the LTS selected TIMPl or TIMP2 siRNA oligos

[00404] Cells are grown as described above. The IC50 value of the tested RNAi activity is determined by constructing a dose-response curve using the activity results obtained with the various final siRNA concentrations. The dose response curve is constructed by plotting the relative amount of residual TIMPl or TIMP2 mRNA versus the logarithm of transfected siRNA concentration. The curve is calculated by fitting the best sigmoid curve to the measured data. The method for the sigmoid fit is also known as a 3 -point curve fit.

where Y is the residual TIMPl or

TIMP2 mRNA response, is the logarithm of transfected siRNA concentration, Bot is the Y value at the bottom plateau, LogIC50 is the X value when 7 is halfway between bottom and top plateaus and HillSlope is the steepness of the curve.

[00406] The percent of inhibition of gene expression using specific siRNAs was determined using qPCR analysis of target gene in cells expressing the endogenous gene. Other siRNA compounds according to Tables Al, A2, A3, A4, A5, A6, A7, A8, Bl, B2, B3, B4, B5, B6, B7, B8 (Tables A1-B8) are tested in vitro where it is shown that these siRNA compounds inhibit gene expression. Activity is shown as percent residual mRNA; accordingly, a lower value reflects better activity.

[00407] In order to test the stability of the siRNA compounds in serum, specific siRNA molecules are incubated in four different batches of human serum (100% concentration) at 37°C for up to 24 hours. Samples are collected at 0.5, 1, 3, 6, 8, 10, 16 and 24 hours. The migration patterns as an indication of are determined at each collection time by

polyacrylamide gel electrophoresis (PAGE).

Example 7

[00408] Validation of siTIMPl and siTIMP2 knock down effect at the protein level [00409] The inhibitory effect of different siTIMPl and siTIMP2 siNA molecules on TIMPl and TIMP2 mRNA expression are validated at the protein level by measuring TIMPl and TIMP2 in hTERT cells transfected with different siTIMPl and siTIMP2. Transfection of hTERT cells with different siTIMPl and siTIMP2 are performed as described above.

Transfected hTERT cells are lysed and the cell lysate are clarified by centrifugation.

Proteins in the clarified cell lysate are resolved by SDS polyacrylamide gel electrophoresis. The level of TIMPl and TIMP2 protein in the cell lysate are determined using anti-TIMP or anti-TIMP2 antibodies as the primary antibody HRP conjugated antibodies (Millipore) as the secondary antibody, and subsequently detection by Supersignal West Pico

Chemiluminescence kit (Pierce). Anti-actin antibody (Abeam) is used as a protein loading control.

Example 8

[00410] Downregulation of Collagen I expression by siTIMPl and siTIMP2 siRNA duplexes.

[00411] To determine the effect of siTIMPl and siTIMP2, alone or in combination on collagen I expression level, collagen I mRNA level in hTERT cells treated with different siTIMPl and or siTIMP2. Briefly, hTERT cells are transfected with different siTIMPl, and or siTIMP2 as described in Example 2. The cells are lysed after 72 hours and mRNA were isolated using RNeasy mini kit according to the manual (Qiagen). The level of collagen 1 mRNA is determined by reverse transcription coupled with quantitative PCR using TaqMan® probes. Briefly, cDNA synthesis is carried out using High-Capacity cDNA Reverse Transcription Kit (ABI) according to the manual, and subjected to TaqMan Gene Expression Assay (ABI, COL1A1 assay ID Hs01076780_gl). The level of collagen I mRNA is normalized to the level of GAPDH mRNA according to the manufacturer's instruction (ABI). The signals are normalized to the signal obtained from cells transfected with scrambled siNA.

Example 9

Immunofluorescence staining of siTIMPl and or siTIMP2 treated hTERT cells

[00412] To visualize the expression of two fibrosis markers, collagen I and alpha-smooth muscle actin (SMA), in hTERT cells transfected, the cells are stained with rabbit anti- collagen I antibody (Abeam) and mouse anti-alpha-SMA antibody (Sigma). Alexa Fluor 594 goat anti-mouse IgG and Alexa Fluor 488 goat anti-rabbit IgG (Invitrogen (Molecular Probes)) are used as secondary antibodies to visualize collagen I (green) and alpha-SMA (red). Hoescht is used to visualize nuleus (blue).

Example 10

Animal models: Model systems of fibrotic conditions

[00413] siRNAs provided herein may be tested in predictive animal models. Rat diabetic and aging models of kidney fibrosis include Zucker diabetic fatty (ZDF) rats, aged fa/fa (obese Zucker) rats, aged Sprague-Dawley (SD) rats, and Goto Kakizaki (GK) rats; GK rats are an inbred strain derived from Wistar rats, selected for spontaneous development of NIDDM (diabetes type II). Induced models of kidney fibrosis include the permanent unilateral ureteral obstruction (UUO) model which is a model of acute interstitial fibrosis occurring in healthy non-diabetic animals; renal fibrosis develops within days following the obstruction. Another induced model of kidney fibrosis is 5/6 nephrectomy model.

[00414] Two models of liver fibrosis in rats are the Bile Duct Ligation (BDL) with sham operation as controls, and CC14 poisoning, with olive oil fed animals as controls, as described in the following references: Lotersztajn S, et al Hepatic Fibrosis: Molecular Mechanisms and Drug Targets. Annu Rev Pharmacol Toxicol. 2004 Oct 07; Uchio K, et al., Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis. Wound Repair Regen. 2004 Jan-Feb;12(l):60-6; Xu XQ, et al, Molecular classification of liver cirrhosis in a rat model by proteomics and bioinformatics Proteomics. 2004 Oct;4(10):3235-45.

[00415] Models for ocular scarring are well known in the art e.g. Sherwood MB et al., J Glaucoma. 2004 Oct;13(5):407-12. A new model of glaucoma filtering surgery in the rat; Miller MH et al, Ophthalmic Surg. 1989 May;20(5):350-7. Wound healing in an animal model of glaucoma fistulizing surgery in the Rb; vanBockxmeer FM et al., Retina. 1985 Fall- Winter; 5(4): 239-52. Models for assessing scar tissue inhibitors; Wiedemann P et al, J Pharmacol Methods. 1984 Aug; 12(1): 69-78. Proliferative vitreoretinopathy: the Rb cell injection model for screening of antiproliferative drugs. [00416] Models of cataract are described in the following publications: The role of Src family kinases in cortical cataract formation. Zhou J, Menko AS. Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2293-300; Bioavailability and anticataract effects of a topical ocular drug delivery system containing disulfiram and hydroxypropyl-beta-cyclodextrin on selenite- treated rats. Wang S, et al. Curr Eye Res. 2004 Jul;29(l):51-8; and Long-term organ culture system to study the effects of UV-A irradiation on lens transglutaminase. Weinreb O, Dovrat A.; Curr Eye Res. 2004 Jul;29(l):51-8.

[00417] The compounds disclosed herein are tested in these models of fibrotic conditions, in which it is found that they are effective in treating liver fibrosis and other fibrotic

conditions. The compounds as described herein are tested in this animal model and the results show that these siRNA compounds are useful in treating and/or preventing ischemia reperfusion injury following lung transplantation.

[00418] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[00419] Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[00420] It will be readily apparent to one skilled in the art that varying substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims. The present disclosure teaches one skilled in the art to test various combinations and/or substitutions of chemical modifications described herein toward generating nucleic acid constructs with improved activity for mediating RNAi activity. Such improved activity can include improved stability, improved bioavailability, and/or improved activation of cellular responses mediating RNAi.

Therefore, the specific embodiments described herein are not limiting and one skilled in the art can readily appreciate that specific combinations of the modifications described herein can be tested without undue experimentation toward identifying nucleic acid molecules with improved R Ai activity.

[00421] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising", "having," "including," containing", etc. shall be read expansively and without limitation (e.g., meaning "including, but not limited to,"). Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[00422] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.