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Title:
METHODS AND COMPOSITIONS FOR NON-VIRAL GENE THERAPY FOR TREATMENT OF HYPERPROLIFERATIVE DISEASES
Document Type and Number:
WIPO Patent Application WO/2000/071096
Kind Code:
A2
Abstract:
The present invention relates to non-viral gene therapy methods and compositions for treatment of hyperproliferative disease in humans. More specifically, the invention is directed, in one embodiment, to lipid formulations which form stable liposome structures, capable of efficient in vivo nucleic acid transfer. In other embodiments, methods and compositions are directed to liposome transfer of anti-proliferative nucleic acids, wherein the transfer of the nucleic acids is cell specific via cell specific targeting moieties. The present invention, thus provides non-viral, liposome compositions and methods of gene transfer particularly useful for targeting and treating hyperproliferative disease.

Inventors:
RAMESH RAJAGOPAL (US)
ROTH JACK A (US)
SAEKI TOMOYUKI (US)
WILSON DEBORAH (US)
Application Number:
PCT/US2000/014350
Publication Date:
November 30, 2000
Filing Date:
May 24, 2000
Export Citation:
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Assignee:
INTROGEN THERAPEUTICS INC (US)
UNIV TEXAS (US)
RAMESH RAJAGOPAL (US)
ROTH JACK A (US)
SAEKI TOMOYUKI (US)
WILSON DEBORAH (US)
International Classes:
A61K9/127; A61K38/17; C12N15/88; A61K48/00; (IPC1-7): A61K9/00
Domestic Patent References:
WO1998007408A11998-02-26
WO1993024640A21993-12-09
WO1998020857A11998-05-22
Other References:
TEMPLETON NANCY SMYTH ET AL: "Improved DNA: Liposome complexes for increased systemic delivery and gene expression." NATURE BIOTECHNOLOGY, vol. 15, no. 7, 1997, pages 647-652, XP002154098 ISSN: 1087-0156
RAMESH RAJAGOPAL ET AL: "Inhibition of primary and disseminated human lung cancers by systemic delivery of p53 tumor suppressor gene using an improved liposome." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, no. 41, March 2000 (2000-03), page 603 XP002154099 91st Annual Meeting of the American Association for Cancer Research.;San Francisco, California, USA; April 01-05, 2000, March, 2000 ISSN: 0197-016X
See also references of EP 1180016A2
Attorney, Agent or Firm:
Shishima, Gina N. (L.L.P. Suite 2400 600 Congress Avenue Austin, TX, US)
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Claims:
WHAT IS CLAIMED IS:
1. A pharmaceutically acceptable lipid formulation comprising DOTAP and at least one cholesterol or cholesterol derivative or cholesterol mixture, in combination with a (a) nucleic acid antisense or ribozyme molecule that inhibits the expression of a growthpromoting polypeptide; or (b) nucleic acid under the control of a promoter and encoding an (1) antiproliferative polypeptide or (2) an antisense molecule or a ribozyme that inhibits the expression of a growthpromoting protein.
2. The formulation of claim 1, comprising DOTAP in a concentration ranging from about 1 to about 8 mM.
3. The formulation of claim 2, comprising DOTAP in a concentration ranging from about 2 to about 7 mM.
4. The formulation of claim 3, comprising DOTAP in a concentration ranging from about 3 to about 6 mM.
5. The formulation of claim 4, comprising DOTAP in a concentration of about 4 to about 5 mM.
6. The formulation of claim 1, comprising the cholesterol or cholesterol derivative or cholesterol mixture in a concentration ranging from about 1 to about 8 mM.
7. The formulation of claim 6, comprising the cholesterol or cholesterol derivative or cholesterol mixture in a concentration ranging from about 2 to about 7 mM.
8. The formulation of claim 7, comprising the cholesterol or cholesterol derivative or cholesterol mixture in a concentration ranging from about 3 to about 6 mM.
9. The formulation of claim 8, comprising the cholesterol or cholesterol derivative or cholesterol mixture in a concentration of about 4 to about 5 mM.
10. The formulation of claim 1, wherein the DOTAP and cholesterol or cholesterol derivative or cholesterol mixture are included in a molar ratio from about 3: 1 to about 1: 3.
11. The formulation of claim 10, wherein the DOTAP and cholesterol or cholesterol derivative or cholesterol mixture are included in a molar ratio of about 1: 1.
12. The formulation of claim 1, wherein the formulation is extruded.
13. The formulation of claim 1, wherein the antiproliferative polypeptide is a tumor suppressor protein.
14. The formulation of claim 13, wherein the tumor suppressor polypeptide is Rb, p53, pl4, pl5, pl6, pl9, INK4c, p21, p27, p73, a pl6p27 fusion, a p21p27 fusion, p56RB, E2F1, NOEY2, DCC, APC, NF1, NF2, PTEN, FHIT, CCAM, Ecadherin, MENI, MEN11, ZAC1, VHL, FCC, MCC, PMS1, PMS2, MLH1, MSH2, DPC4, BRCA1, BRCA2, mda7, DBCCR1 or WT1.
15. The formulation of claim 14, wherein the tumor suppressor polypeptide is p53.
16. The formulation of claim 1, wherein the growth promoting polypeptide is a growth factor receptor.
17. The formulation of claim 1, wherein the antiproliferative polypeptide is a single chain antibody, a decoy, or a dominant negative directed to a growth factor receptor.
18. The formulation of claim 17, wherein the growth factor receptor is FMS, ERBB/HER, ERBB2/NEU/HER2, ERBA, TGFP receptor, PDGF receptor, MET, KIT or TRK.
19. The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of a growth factor receptor.
20. The formulation of claim 19, wherein the growth factor receptor is FMS, ERBB/HER, ERBB2/NEU/HER2, ERBA, TGFP receptor, PDGF receptor, MET, KIT or TRK.
21. The formulation of claim 1, wherein the antiproliferative polypeptide is a single chain antibody, a decoy, or a dominant negative directed to a signal transducing protein.
22. The formulation of claim 21, wherein the signal transducing protein is SRC, ABL, RAS, AKT/PKB, RSK1, RSK2, RSK3, RSKB, PRAD, LCK, or ATM.
23. The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of a signal transducing protein.
24. The formulation of claim 23, wherein the signal transducing protein is SRC, ABL, RAS, AKT/PKB, RSK1, RSK2, RSK3, RSKB, PRAD, LCK, or ATM.
25. The formulation of claim 1, wherein the antiproliferative polypeptide is a single chain antibody, a decoy, or a dominant negative directed to a transcription factor.
26. The formulation of claim 25, wherein the transcription factor is JUN, FOS, MYC, BRCA1, BRCA2, ERBA, ETS, EVII, MYB, HMGIC, HMGG/LIM, SKI, VHL, WT1, CEBPa, NFKB, IxB, GL1, orREL.
27. 25 The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of a transcription factor protein.
28. The formulation of claim 25, wherein the transcription factor protein is JUN, FOS, MYC, BRCA1, BRCA2, ERBA, ETS, EVII, MYB, HMGIC, HMGG/LIM, SKI, VHL, WT1, CEBPa, NFKB, IxB, GL1, or REL.
29. The formulation of claim 1, wherein the antiproliferative polypeptide is a single chain antibody, a decoy, or a dominant negative directed to a growth factor.
30. The formulation of claim 28, wherein the growth factor is SIS, HST, INT1/WT1, or INT2.
31. The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of a growth factor.
32. The formulation of claim 30, wherein the growth factor is SIS, HST, INT1/WT1, or INT2.
33. The formulation of claim 1, wherein the antiproliferative polypeptide is an apoptotic factor protein.
34. The formulation of claim 32, wherein the apoptotic factor protein is Bax, Bak, Bim, Bik, BclxL, BclxS, Bid, Bad, Bcl2, Harakiri, or an ICE protease.
35. The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of an apoptotic factor protein.
36. The method of claim 34, wherein the apoptotic factor protein is Bax, Bak, Bim, Bik, BclxL, BclxS, Bid, Bad, Bcl2, Harakiri, or an ICE protease.
37. The formulation of claim 1, wherein the antiproliferative polypeptide is a single chain antibody, a decoy, or a dominant negative directed to a tumorassociated protein.
38. The formulation of claim 36, wherein the tumorassociated protein is CEA, mucin, MAGE, or GAGE.
39. The formulation of claim 1, wherein the antisense molecule or ribozyme inhibits the expression of a tumorassociated protein.
40. The formulation of claim 38, wherein the tumorassociated protein is CEA, mucin, MAGE, or GAGE.
41. The formulation of claim 1, further comprising a targeting moiety.
42. The formulation of claim 40, wherein the targeting moiety is a peptide, a ligand, or an antibody.
43. The formulation of claim 41, wherein the targeting moiety comprises a peptide that includes an RGD sequence.
44. The formulation of claim 42, wherein the peptide includes an RGDFV sequence.
45. The formulation of claim 43, wherein the peptide is from 3 to 30 amino acids in length.
46. The formulation of claim 44, wherein the peptide is from 3 to 20 amino acids in length.
47. The formulation of claim 45, wherein the peptide is from 4 to 10 amino acids in length.
48. The formulation of claim 43, wherein the peptide is a cyclic peptide.
49. The formulation of claim 47, wherein the cyclic peptide is 5 amino acids in length.
50. The formulation of claim 41, wherein the targeting moiety comprises a ligand that is a substrate for a cell surface protein.
51. The formulation of claim 49, wherein the cell surface protein is an integrin, proteoglycan, glycoprotein, receptor, or transporter.
52. The formulation of claim 41, wherein the targeting moiety comprises an antibody that binds to a cell surface protein.
53. The formulation of claim 51, wherein the antibody is an antibody to the Her1 receptor.
54. The formulation of claim 1, wherein the promoter is CMV IE, CEA, VEGF, AFP, lung surfactant promoter, dectinl, dectin2, human CDl lc, F4/80, SM22, CEA, tyrosinase, tetinducible or tetrepressible, RSV, MLP, or MHC class II promoter.
55. A method of treating a hyperproliferative disorder comprising administering an effective amount of the formulation of claim 1 to a patient in need of antiproliferative therapy.
56. The method of claim 54, wherein the hyperproliferative disease is cancer.
57. The method of claim 55, wherein the cancer is lung, head and neck, pancreatic, prostate, renal, bone, testicular, breast, cervical, gastrointestinal, lymphoma, brain, breast, ovarian, leukemia, myeloma, colorectal, esophageal, skin, thyroid, liver, or bladder cancer.
58. The method of claim 54, wherein the hyperproliferative disease is rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, adenoma, leiomyoma, lipoma, hemangioma, fibroma, restenosis, preneoplastic lesions, vascular occlusion, or psoriasis.
59. The method of claim 54, wherein the hyperproliferative disorder is vascular occlusion.
60. The method of claim 58, wherein the hyperproliferative disorder is restenosis.
61. The method of claim 55, wherein the formulation is administered to the patient by intratumoral injection, intratracheal injection, intravenous injection, intraperitoneal injection, intravesical instillation, intraarterial infusion, intrapericardial injection, intramuscular injection, topical application, aerosolization, mucosal exposure, orally, or lavage.
62. The method of claim 54, wherein the formulation is administered more than one time.
63. The method of claim 60, wherein the formulation is administered to the patient by intratumoral injection.
64. The method of claim 60, wherein the formulation is administered intravenously to the patient.
65. The method of claim 55, wherein the cancer comprises a tumor.
66. The method of claim 64, wherein the formulation is administered to a tumor bed prior to or after resection of the tumor.
67. The method of claim 65, wherein the formulation is administered to the tumor bed both prior to and after tumor resection.
68. The method of claim 54, wherein the formulation is administered to the patient before chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
69. The method of claim 54, wherein the formulation is administered during chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
70. The method of claim 54, wherein the formulation is administered after chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
71. The method of claim 69, wherein the formulation is administered less than 72 hours prior to chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
72. The method of claim 70, wherein the formulation is administered less than 24 hours prior to chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
73. The method of claim 71, wherein the formulation is administered less than 72 hours after chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
74. The method of claim 72, wherein the formulation is administered less than 24 hours after chemotherapy, surgery, immunotherapy, hormonal therapy, or radiotherapy.
Description:
INTERNATIONAL SEARCH REPORT Intei mal Application No PCT/US00/14350 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category o Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO 98 20857 A (UNIV CALIFORNIA) 1-74 22 May 1998 (1998-05-22) abstract page 14, line 10-line 11 page 18, line 21-page 22, line 29 page 32, line 6-line 29 A TEMPLETON NANCY SMYTH ET AL:"Improved DNA: Liposome complexes for increased systemic delivery and gene expression." NATURE BIOTECHNOLOGY, vol. 15, no. 7,1997, pages 647-652, XP002154098 ISSN: 1087-0156 the whole document P, X RAMESH RAJAGOPAL ET AL:"Inhibition of 1-74 primary and disseminated human lung cancers by systemic delivery of p53 tumor suppressor gene using an improved liposome." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, no. 41, March 2000 (2000-03), page 603 XP002154099 91st Annual Meeting of the American Association for Cancer Research.; San Francisco, California, USA; April 01-05, 2000, March, 2000 ISSN: 0197-016X the whole document 1 INTERNATIONAL SEARCH REPORT inter) nal Application No information on patent family members PCT/US OOI14350 Patent document Publication Patent Publication cited in search report date member (s) date WO 9807408 A 26-02-1998 AU 4050297 A 06-03-1998 EP 0955999 A 17-11-1999 WO 9324640 A 09-12-1993 AU 1912897 A 26-06-1997 AU 3467193 A 19-07-1993 AU 672412 B 03-10-1996 AU 4407593 A 30-12-1993 AU 4528493 A 04-01-1994 CA 2126101 A 24-06-1993 CA 2134773 A 09-12-1993 EP 0625207 A 23-11-1994 EP 0646178 A 05-04-1995 JP 7507450 T 24-08-1995 JP 7502510 T 16-03-1995 WO 9312240 A 24-06-1993 WO 9325673 A 23-12-1993 US 5827703 A 27-10-1998 US 6001644 A 14-12-1999 WO 9820857 A 22-05-1998 AU 7177998 A 03-06-1998 EP 0956001 A 17-11-1999



 
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