MILLER JEFFREY CHRISTOPHER (US)
WO2008006028A2 | 2008-01-10 | |||
WO2014039585A2 | 2014-03-13 | |||
WO1995019431A1 | 1995-07-20 | |||
WO1996006166A1 | 1996-02-29 | |||
WO1998053057A1 | 1998-11-26 | |||
WO1998053058A1 | 1998-11-26 | |||
WO1998053059A1 | 1998-11-26 | |||
WO1998053060A1 | 1998-11-26 | |||
WO1998054311A1 | 1998-12-03 | |||
WO2000027878A1 | 2000-05-18 | |||
WO2001060970A2 | 2001-08-23 | |||
WO2001088197A2 | 2001-11-22 | |||
WO2002016536A1 | 2002-02-28 | |||
WO2002099084A2 | 2002-12-12 | |||
WO2003016496A2 | 2003-02-27 | |||
WO2018013840A1 | 2018-01-18 | |||
WO2012068380A2 | 2012-05-24 |
US5789538A | 1998-08-04 | |||
US5925523A | 1999-07-20 | |||
US6007988A | 1999-12-28 | |||
US6013453A | 2000-01-11 | |||
US6140081A | 2000-10-31 | |||
US6200759B1 | 2001-03-13 | |||
US6453242B1 | 2002-09-17 | |||
US6534261B1 | 2003-03-18 | |||
US6979539B2 | 2005-12-27 | |||
US8586526B2 | 2013-11-19 | |||
US20180087072A1 | 2018-03-29 | |||
US20130253040A1 | 2013-09-26 | |||
US20150335708A1 | 2015-11-26 | |||
US20160296605A1 | 2016-10-13 | |||
US9943565B2 | 2018-04-17 | |||
US7939327B2 | 2011-05-10 | |||
US6503717B2 | 2003-01-07 | |||
US6599692B1 | 2003-07-29 | |||
US6607882B1 | 2003-08-19 | |||
US6689558B2 | 2004-02-10 | |||
US6824978B1 | 2004-11-30 | |||
US6933113B2 | 2005-08-23 | |||
US7013219B2 | 2006-03-14 | |||
US7163824B2 | 2007-01-16 |
SAMBROOK ET AL.: "MOLECULAR CLONING: A LABORATORY MANUAL", 1989, COLD SPRING HARBOR LABORATORY PRESS
AUSUBEL ET AL.: "CURRENT PROTOCOLS IN MOLECULAR BIOLOGY", 1987, JOHN WILEY & SONS
NUNES-DUBY, S. E. ET AL., NUCLEIC ACIDS RESEARCH, vol. 26, 1998, pages 391 - 406
"METHODS IN ENZYMOLOGY", vol. 304, 1999, ACADEMIC PRESS, article "Chromatin"
"METHODS IN MOLECULAR BIOLOGY", vol. 119, 1999, HUMANA PRESS, article "Chromatin Protocols"
ESPOSITO, D.SCOCCA, J. J., NUCLEIC ACIDS RESEARCH, vol. 25, 1997, pages 3605 - 3614
STARK, W. M. ET AL., TRENDS IN GENETICS, vol. 8, 1992, pages 432 - 439
PLASTERK R.H. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 81, 1984, pages 2689 - 2692
SMITH MC ET AL., MOL MICROBIOL, vol. 44, 2002, pages 299 - 307
PABO ET AL., ANNU REV BIOCHEM, vol. 70, 2001, pages 313 - 40
SADELAIN ET AL., NAT REV CANCER, vol. 12, no. 1, 2012, pages 51 - 8
FRESHNEY ET AL.: "Culture of Animal Cells, A Manual of Basic Technique", 1994
INABA ET AL., J. EXP. MED., vol. 176, 1992, pages 1693 - 1702
"Virology", 1988
"Fundamental Virology", 1991
CHADWICK ET AL., GENE THERAPY, vol. 4, 1997, pages 1289 - 1299
GAOHUANG, GENE THERAPY, vol. 2, 1995, pages 710 - 722
ONODERA ET AL., BLOOD, vol. 91, 1998, pages 30 - 36
FINGL ET AL.: "The Pharmacological Basis of Therapeutics", 1975, pages: 1
MILLER ET AL.: "Enhancing gene editing specificity by attenuating DNA cleavage kinetics", NATURE BIOTECHNOLOGY, vol. 37, 2019, XP036849997, DOI: 10.1038/s41587-019-0186-z
What is Claimed is: 1. A Gin recombinase catalytic domain variant comprising a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 2. The Gin recombinase catalytic domain variant according to claim 1, further comprising a His106Tyr amino acid substitution. 3. The Gin recombinase catalytic domain variant according to claim 2, comprising the amino acid sequence set forth in any one of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 56, or SEQ ID NO: 60. 4. The Gin recombinase catalytic domain variant according to claim 1, further comprising an Ile94Val amino acid substitution. 5. The Gin recombinase catalytic domain variant according to claim 4, comprising the amino acid sequence set forth in any one of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 57, or SEQ ID NO: 61. 6. A polynucleotide encoding a Gin recombinase catalytic domain variant, wherein the nucleic acid sequence encoding the Gin recombinase catalytic domain variant comprises the nucleotide sequence set forth in SEQ ID NO: 7. 7. A polynucleotide encoding a Gin recombinase catalytic domain variant according to any one of claims 1-5. 8. A zinc-finger recombinase, comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 9. The zinc finger recombinase according to claim 8, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution. 10. The zinc finger recombinase according to claim 9, wherein the Gin recombinase catalytic domain variant comprises the amino acid sequence set forth in any one of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 56, or SEQ ID NO: 60. 11. The zinc finger recombinase according to claim 8, wherein the Gin recombinase catalytic domain variant further comprises an Ile94Val amino acid substitution. 12. The zinc finger recombinase according to claim 11, wherein the Gin recombinase catalytic domain variant comprises the amino acid sequence set forth in any one of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 57, or SEQ ID NO: 61. 13. The zinc-finger recombinase according to any one of claims 8-12, wherein the zinc-finger recombinase protein is a multimeric protein. 14. The zinc-finger recombinase according to claim 13, wherein the zinc-finger recombinase protein is a homomultimeric protein. 15. The zinc-finger recombinase according to claim 13, wherein the zinc-finger recombinase protein is a heteromultimeric protein. 16. The zinc-finger recombinase according to claim 13, wherein said zinc-finger recombinase protein is a dimeric protein. 17. The zinc-finger recombinase according to claim 16, wherein said zinc-finger recombinase protein is a homodimeric protein. 18. The zinc-finger recombinase according to claim 16, wherein said zinc-finger recombinase protein is a heterodimeric protein. 19. The zinc-finger recombinase according to claim 14, wherein said zinc-finger recombinase protein is a tetrameric protein. 20. The zinc-finger recombinase according to claim 19, wherein said zinc-finger recombinase protein is a homotetrameric protein. 21. The zinc-finger recombinase according to claim 19, wherein said zinc-finger recombinase protein is a heterotetrameric protein. 22. The zinc-finger recombinase according to any one of claims 8 to 21, wherein the zinc finger nucleotide binding domain comprises the sequence as set forth in SEQ ID NO: 9 or SEQ ID NO: 10. 23. The zinc-finger recombinase according to any one of claims 8 to 22, wherein the zinc finger recombinase protein binds a nucleotide sequence comprising the sequence as set forth in SEQ ID NO: 15. 24. The zinc-finger recombinase according to any one of claims 8 to 23, wherein the zinc finger nucleotide binding domain is capable of binding an endogenous locus. 25. The zinc-finger recombinase according to claim 24, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC) gene, Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. 26. A polynucleotide encoding the zinc-finger recombinase according to any one of claims 8-25. 27. The polynucleotide according to claim 26, wherein the nucleic acid sequence encoding the Gin recombinase catalytic domain variant comprises the nucleotide sequence set forth in SEQ ID NO: 7. 28. A vector comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to claims 6-7. 29. A vector comprising the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 30. A cell comprising the vector according to claim 28 or 29. 31. A cell comprising the Gin recombinase catalytic domain variant according to any one of claims 1-5. 32. A cell comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to claims 6-7. 33. A cell comprising the zinc finger recombinase protein according to any one of claims 8-25. 34. A cell comprising the polynucleotide encoding the zinc-finger recombinase according to claim 26-27. 35. The cell according to any one of claims 30 to 34, wherein the cell is a eukaryotic cell. 36. The cell according to claim 35, wherein the cell is a mammalian cell. 37. The cell according to claim 36, wherein the wherein the cell is a stem cell. 38. The cell according to claim 35, wherein the cell is a human cell. 39. A pharmaceutical composition comprising the Gin recombinase catalytic domain variant according to any one of claims 1-5; and a pharmaceutically acceptable carrier. 40. A pharmaceutical composition comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to claim 6-7; and a pharmaceutically acceptable carrier. 41. A pharmaceutical composition comprising the zinc-finger recombinase according to any one of claims 8 to 25; and a pharmaceutically acceptable carrier. 42. A pharmaceutical composition comprising the polynucleotide encoding a zinc- finger recombinase according to claim 26 or 27; and a pharmaceutically acceptable carrier. 43. A method for modifying the genome of a cell, the method comprising introducing into a cell the zinc-finger recombinase according to any one of claims 8-25. 44. A method for modifying the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 45. A method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell, the method comprising introducing into a cell the zinc-finger recombinase according to any one of claims 8-25. 46. A method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 47. A method for disrupting a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the zinc-finger recombinase according to any one of claims 8-25. 48. A method for disrupting a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 49. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell the zinc-finger recombinase according to any one of claims 8-25. 50. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 51. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 52. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 53. The method according to any one of claims 49-52, further comprising introducing into the cell a non-homologous end joining (NHEJ) inhibitor. 54. The method according to claim 53, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 55. The method according to claim 54, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 56. A method for treating a disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the zinc-finger recombinase according to any one of claims 8-25. 57. A method for treating a disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 58. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc- finger recombinase according to any one of claims 8-25. 59. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 60. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 61. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 62. The method according to any one of claims 58-61, further comprising administering a non-homologous end joining (NHEJ) inhibitor. 63. The method according to claim 62, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 64. The method according to claim 63, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 65. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell comprising introducing into the cell the zinc-finger recombinase according to any one of claims 8-25. 66. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 67. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc-finger recombinase according to any one of claims 8-25. 68. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence in the genome of the cell by introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27. 69. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 70. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence in the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 71. The method according to any one of claims 67-70, wherein the method further comprises a non-homologous end joining (NHEJ) inhibitor. 72. The method according to claim 71, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 73. The method according to claim 72, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 74. The method according to any one of claims 43 to 73, wherein the cell is a eukaryotic cell. 75. The method according to claim 74, wherein the cell is a mammalian cell. 76. The method according to claim 75, wherein the cell is a stem cell. 77. The method according to claim 74, wherein the cell is a human cell. 78. The method according to any one of claims 43 to 73, wherein the method is independent of Fis. 79. The method according to any one of claims 43 to 78, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. 80. The method according to any one of claims 45 to 78, wherein the target nucleotide sequence is an endogenous locus. 81. The method according to claim 80, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. 82. The zinc-finger recombinase according to any one of claims 8-25 for use in modifying the genome of a cell. 83. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in modifying the genome of a cell. 84. The zinc-finger recombinase according to any one of claims 8-25 for use in integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. 85. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. 86. The zinc-finger recombinase according to any one of claims 8-25 for use in disrupting a target nucleotide sequence in the genome of a cell. 87. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in disrupting a target nucleotide sequence in the genome of a cell. 88. The zinc-finger recombinase according to any one of claims 8-25 for use in excising a target nucleotide sequence from the genome of a cell. 89. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in excising a target nucleotide sequence from the genome of a cell. 90. A zinc finger recombinase for use in excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 91. A polynucleotide encoding a zinc-finger recombinase for use in excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 92. The zinc finger recombinase for use according to claim 88 or 90 or polynucleotide encoding a zinc finger recombinase according to claim 89 or 91, further comprising the use of a non-homologous end joining (NHEJ) inhibitor. 93. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 92, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 94. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 93, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 95. The zinc-finger recombinase according to any one of claims 8-25 for use in treating a disorder in a subject by modifying a target sequence in the genome of the cell. 96. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in treating a disorder in a subject by modifying a target sequence in the genome of the cell. 97. The zinc-finger recombinase according to any one of claims 8-25 for use in treating a disorder in a subject by excising a target sequence from the genome of the cell. 98. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in treating a disorder in a subject, by excising a target sequence from the genome of the cell. 99. A zinc-finger recombinase for use in treating a disorder in a subject, by excising a target sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 100. A polynucleotide encoding a zinc-finger recombinase for use in treating a disorder in a subject, by excising a target sequence from the genome of a cell , wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 101. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 97-100, for use with a non- homologous end joining (NHEJ) inhibitor. 102. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 101, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 103. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 102, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 104. The zinc-finger recombinase according to any one of claims 8-25 for use in correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. 105. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. 106. The zinc-finger recombinase according to any one of claims 8-25 for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell. 107. The polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 for use in correcting a disease-causing mutation in the genome of a cell. 108. A zinc finger recombinase for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 109. A polynucleotide encoding a zinc-finger recombinase for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 110. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 106-109, for use with a non- homologous end joining (NHEJ) inhibitor. 111. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 110, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 112. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 111, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 113. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 82-112, wherein the cell is a eukaryotic cell. 114. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 113, wherein the cell is a mammalian cell. 115. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 114, wherein the cell is a stem cell. 116. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 113, wherein the cell is a human cell. 117. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 82-116, wherein the use is independent of Fis. 118. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 82-117, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. 119. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of claims 84-118, wherein the target nucleotide sequence is an endogenous locus. 120. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to claim 119, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. 121. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for modifying the genome of a cell. 122. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for modifying the genome of a cell. 123. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. 124. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. 125. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for disrupting a target nucleotide sequence in the genome of a cell. 126. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for disrupting a target nucleotide sequence in the genome of a cell. 127. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell. 128. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell. 129. Use of a zinc finger recombinase in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 130. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 131. The use according to any one of claims 127-130, further comprising the use of a non-homologous end joining (NHEJ) inhibitor. 132. The use according to claim 131, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 133. The use according to claim 132, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 134. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for treating a disorder in a subject by modifying a target sequence in the genome of the cell. 135. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for treating a disorder in a subject by modifying a target sequence in the genome of the cell. 136. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for treating a disorder in a subject by excising a target sequence from the genome of the cell. 137. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of the cell. 138. Use of a zinc-finger recombinase in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 139. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 140. The use according to any one of claims 136-139, for use with a non-homologous end joining (NHEJ) inhibitor. 141. The use according to claim 140, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 142. The use according to claim 141, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 143. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. 144. Use of a polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. 145. Use of the zinc-finger recombinase according to any one of claims 8-25 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell. 146. Use of the polynucleotide encoding a zinc-finger recombinase according to claim 26 or 27 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell. 147. Use of a zinc finger recombinase in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 148. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. 149. The use according to any one of claims 145-148, for use with a non-homologous end joining (NHEJ) inhibitor. 150. The use according to claim 149, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. 151. The use according to claim 150, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. 152. The use according to any one of claims 121-151, wherein the cell is a eukaryotic cell. 153. The use according to claim 152, wherein the cell is a mammalian cell. 154. The use according to claim 153, wherein the cell is a stem cell. 155. The use according to claim 152, wherein the cell is a human cell. 156. The use according to any one of claims 121-155, wherein the use is independent of Fis. 157. The use according to any one of claims 121-156, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. 158. The use according to any one of claims 121-157, wherein the target nucleotide sequence is an endogenous locus. 159. The use according to claim 158, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. |
[00185] In some embodiments, the polynucleotide sequence encoding the Gin recombinase catalytic domain variant included in the ZFR comprises the sequence set forth in SEQ ID NO: 7 below, which encodes the Gin recombinase catalytic domain comprising a Phe104Asn substitution with respect to the Gin recombinase catalytic domain (SEQ ID NO: 6): [00186] [00187] In some embodiments, the Gin recombinase nucleotide sequence included in the nucleotide sequence encoding a ZFR of the disclosure comprises at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more sequence identity to the reference SEQ ID NO: 7, as determined by sequence alignment programs known by skilled artisans. [00188] In some embodiments, the catalytic domain of the Gin recombinase protein is operably linked to a zinc-finger nucleotide binding domain. Optionally, the catalytic domain of the Gin recombinase protein is connected by way of a linker to the zinc-finger nucleotide binding domain, wherein said recombinase is capable of binding a target nucleic acid sequence by way of said zinc-finger nucleotide binding domain. In some embodiments, the linker region is a sequence with structural flexibility. In some embodiments, the linker region comprises at least 3, at least 6, at least 10, at least 20, at least 30 or at least 40 amino acids in length. Preferably, the nucleic acid is 3, 4, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 or 45 amino acids in length. In some embodiments, the sequence of the linker is the sequence set forth in SEQ ID NO: 8 (KSGTG). In some embodiments, a 3x FLAG (DYKDHDGDYKDHDIDYKDDDDK; SEQ ID NO: 18) and SV40 NLS (PKKKRKV; SEQ ID NO: 19) sequences are included upstream of the γ Gin recombinase protein sequence. [00189] In some embodiments, the polynucleotide encoding the zinc-finger recombinase protein comprises a polynucleotide encoding the catalytic domain of Gin recombinase protein operably linked to a zinc-finger nucleotide binding domain. Optionally, the polynucleotide encoding the catalytic domain of the Gin recombinase protein is connected by way of a linker to the zinc-finger nucleotide binding domain. In some embodiments, the linker comprises at least 6, at least 10, at least 20, at least 30 or at least 40 base pairs in length. Preferably, the nucleic acid is 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 or 45 base pairs in length. [00190] A “zinc finger protein” or “ZFP” refers to a protein having zinc finger nucleotide binding domains that are stabilized by zinc. ZFPs bind to DNA in a sequence-specific manner. The individual DNA-binding domains are referred to as “fingers.” A ZFP has at least one finger, each finger binds from two to four base pairs of DNA, typically three or four base pairs of DNA. Each zinc finger typically comprises approximately 30 amino acids and chelates zinc. A ZFP may be engineered to have a novel binding specificity, compared to a naturally-occurring zinc finger protein. Engineering methods include, but are not limited to, rational design and various types of selection. Rational design includes, for example, using databases comprising triplet (or quadruplet) nucleotide sequences and individual zinc finger amino acid sequences, in which each triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers that bind the particular triplet or quadruplet sequence. See, e.g., ZFP design methods described in detail in U.S. Pats.5,789,538; 5,925,523; 6,007,988; 6,013,453; 6,140,081; 6,200,759; 6,453,242; 6,534,261; 6,979,539; and 8,586,526; and International Patent Publications WO 95/19431; WO 96/06166; WO 98/53057; WO 98/53058; WO 98/53059; WO 98/53060; WO 98/54311; WO 00/27878; WO 01/60970; WO 01/88197; WO 02/016536; WO 02/099084; and WO 03/016496. [00191] Zinc finger nucleotide binding domains (ZFPs) include at least one zinc finger but can include a plurality of zinc fingers (e.g., 2, 3, 4, 5, 6 or more fingers). Usually, the ZFPs include at least three fingers. Certain of the ZFPs include four, five or six fingers, while some ZFPs include 8, 9, 10, 11 or 12 or more fingers. The ZFPs that include three fingers typically recognize a target site that includes 9 or 10 nucleotides; ZFPs that include four fingers typically recognize a target site that includes 12 to 14 nucleotides; while ZFPs having six fingers can recognize target sites that include 18 to 21 nucleotides. The ZFPs can also be fusion proteins that include one or more functional (regulatory) domains, which domains can be transcriptional activation or repression domains or other domains such as DNMT domains. The DNA binding domains fused to at least one regulatory (functional) domain and can be thought of as a ‘ZFP-TF’ architecture. Selection of target sites; ZFPs and methods for design and construction of zinc-finger recombinase proteins (and polynucleotides encoding same) are known to those of skill in the art and described in detail in U.S. Patent Nos.6,140,081; 5,789,538; 6,453,242; 6,534,261; 5,925,523; 6,007,988; 6,013,453; 6,200,759; and International Patent Publication Nos. WO 95/19431; WO 96/06166; WO 98/53057; WO 98/54311; WO 00/27878; WO 01/60970; WO 01/88197; WO 02/099084; WO 98/53058; WO 98/53059; WO 98/53060; WO 02/016536; and WO 03/016496. [00192] Methods and compositions can also be used to increase the specificity of a ZFP for its intended target relative to other unintended cleavage sites, known as off-target sites for example by mutations to the ZFP backbone as described in U.S. Patent Publication No.20180087072. Thus, zinc finger nucleotide binding domains described herein can comprise mutations in one or more of their DNA binding domain backbone regions. These ZFPs can include mutations to amino acid within the ZFP DNA binding domain (‘ZFP backbone’) that can interact non-specifically with phosphates on the DNA backbone, but they do not comprise changes in the DNA recognition helices. Thus, the invention includes mutations of cationic amino acid residues in the ZFP backbone that are not required for nucleotide target specificity. In some embodiments, these mutations in the ZFP backbone comprise mutating a cationic amino acid residue to a neutral or anionic amino acid residue. In some embodiments, these mutations in the ZFP backbone comprise mutating a polar amino acid residue to a neutral or non-polar amino acid residue. In some embodiments, mutations at made at position (-5), (-9) and/or position (-14) relative to the DNA binding helix. In some embodiments, a zinc finger may comprise one or more mutations at (-5), (-9) and/or (-14). In further embodiments, one or more zinc finger in a multi-finger zinc finger protein may comprise mutations in (-5), (-9) and/or (-14). In some embodiments, the amino acids at (-5), (-9) and/or (-14) (e.g. an arginine (R) or lysine (K)) are mutated to an alanine (A), leucine (L), Ser (S), Asp (N), Glu (E), Tyr (Y) and/or glutamine (Q). [00193] In some embodiments, the left arm of the zinc finger nucleotide binding domain comprises the amino acid sequence set forth in SEQ ID NO: 9 below: [00194] In some embodiments, the right arm of zinc finger nucleotide binding domain comprises the amino acid sequence set forth in SEQ ID NO: 10 below: [00195] In some embodiments, the amino acid sequence of the left arm of the zinc-finger recombinase protein of the disclosure comprises the sequence set forth below (SEQ ID NO: 64), where the Gin recombinase F104N variant catalytic domain amino acid sequence is depicted in bold, the zinc-finger protein amino acid sequence is depicted in italics and the linker is underlined. L P E K [00196] In some embodiments, the amino acid sequence of the right arm of the zinc-finger recombinase protein of the disclosure is the sequence set forth below (SEQ ID NO: 65), where the Gin recombinase F104N variant catalytic domain amino acid sequence is depicted in bold, the zinc-finger protein amino acid sequence is depicted in italics and the linker is underlined. [00197] In some embodiments, the amino acid sequence of the left arm of the zinc-finger recombinase protein of the disclosure comprises the sequence set forth below (SEQ ID NO: 4), where the Gin recombinase F104N variant catalytic domain amino acid sequence is depicted in bold, the zinc-finger protein amino acid sequence is depicted in italics and the linker is underlined. In some embodiments, a 3x FLAG (DYKDHDGDYKDHDIDYKDDDDK; SEQ ID NO: 18) and SV40 NLS (PKKKRKV; SEQ ID NO: 19) sequences are included upstream of the γ Gin recombinase protein sequence. KDHDGDYKDHDIDYKDDDDKAPKKKRKVDMLIGYVRVSTNDQNTDL ALVCAGCEQIFEDKLSGTRTDRPGLKRALKRLQKGDTLVVWKLDR SMKHLISLVGELRERGINFRSLTDSIDTSSPMGRFNFHVMGALAEME LERVMAGIAAARNKGRRWGRPPKSGTGERPFQCRICMRNFSRPYTLRL S SR [00198] In some embodiments, the amino acid sequence of the right arm of the zinc-finger recombinase protein of the disclosure is the sequence set forth below (SEQ ID NO: 5), where the Gin recombinase F104N variant catalytic domain amino acid sequence is depicted in bold, the zinc-finger protein amino acid sequence is depicted in italics and the linker is underlined. In some embodiments, a 3x FLAG (DYKDHDGDYKDHDIDYKDDDDK; SEQ ID NO: 18) and SV40 NLS (PKKKRKV; SEQ ID NO: 19) sequences are included upstream of the γ Gin recombinase protein sequence. [00199] In some embodiments, the zinc finger nucleotide binding domain binds an endogenous locus. In some embodiments, the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC) and a safe-harbor locus. In some embodiments, the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. In some embodiments, the safe-harbor locus is in chromosome 1. [00200] In some embodiments, the zinc finger nucleotide binding domain binds an HPRT gene. In some embodiments, the HPRT zinc finger recombinase protein donor plasmid comprises the nucleotide sequence set forth in SEQ ID NO: 11:
[00201] The zinc-finger recombinase protein promotes site-specific recombination between DNA targets that consist of two zinc-finger binding sites flanking a central 20-bp core sequence recognized by the recombinase catalytic domain. In some embodiments, the 20-bp core sequence recognized by the Gin recombinase catalytic domain of the disclosure comprises the nucleotide sequence set forth in SEQ ID NO: 12: GTTATAACTTTACTTTTAAT. In some embodiments, the two zinc-finger binding sites comprise the nucleotide sequence set forth in SEQ ID NO: 13 (AAGGTGGAAGCTTTACTTG) and SEQ ID NO: 14 (ACCTAGAACAGTGAGTCTTC), respectively. In some embodiments, the full target site of the zinc-finger recombinase protein comprises the nucleotide sequence set forth in SEQ ID NO: 15: T [00202] In some embodiments, the disclosure provides a pVAX plasmid comprising a polynucleotide encoding the left arm of a zinc finger recombinase protein. In some embodiments, the nucleotide sequence of the plasmid encoding the left arm of a zinc-finger recombinase protein comprises the sequence set forth in SEQ ID NO: 16: [00203] In some embodiments, the disclosure provides a pVAX plasmid comprising a polynucleotide encoding the right arm of a zinc finger recombinase protein. In some embodiments, the nucleotide sequence of the plasmid encoding the right arm of a zinc-finger recombinase protein comprises the sequence set forth in SEQ ID NO: 17: [00204] Also provided herein are vectors comprising polynucleotide sequences encoding the zinc-finger recombinase protein as described herein. Suitable vectors include, but are not limited to, a plasmid, a viral vector, a mini-circle and a linear DNA form. Host cells containing said polynucleotide sequences or vectors are also provided. Any of the foregoing zinc-finger recombinase proteins, polynucleotides encoding the zinc-finger recombinase protein, vectors or cells may be used in the methods disclosed herein. [00205] Another aspect of the present disclosure relates to a pharmaceutical composition comprising the zinc-finger recombinase protein of the disclosure, which comprises a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35; and a pharmaceutically acceptable carrier. [00206] In another aspect, the disclosure relates to a pharmaceutical composition comprising a polynucleotide encoding the zinc-finger recombinase protein of the disclosure, which comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35; and a pharmaceutically acceptable carrier. [00207] Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions available, as described below (see, e.g., Remington’s Pharmaceutical Sciences, 17th ed., 1989). Methods for modifying the genome of a cell [00208] In one aspect, the present disclosure provides methods for modifying the genome of a cell, the method comprising introducing into the cell the Gin recombinase catalytic domain variant of the disclosure zinc-finger recombinase protein of the disclosure or a polynucleotide encoding the Gin recombinase catalytic domain variant or the zinc-finger recombinase protein of the disclosure. The zinc- finger recombinase proteins (ZFR) of the disclosure are chimeric proteins capable of introducing targeted modifications into cells. ZFRs promote site-specific recombination between DNA targets that consist of two zinc-finger binding sites flanking a central 20-bp core sequence recognized by the recombinase catalytic domain. The customization of the zinc-finger nucleotide binding domains allows for the design of ZFRs that have the capacity of recognizing a broad range of defined DNA targets and direct site-specific integration into endogenous genomic loci. [00209] In another aspect, the present disclosure provides a method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell, the method comprising introducing into a cell the Gin recombinase catalytic domain variant of the disclosure or the zinc-finger recombinase protein of the disclosure. [00210] In another aspect, the present disclosure provides a method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in a gene of a cell, the method comprising introducing into a cell the Gin recombinase catalytic domain variant of the disclosure or the zinc-finger recombinase protein of the disclosure. [00211] In another aspect, the present disclosure provides a method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell, the method comprising introducing into a cell a polynucleotide encoding the Gin recombinase catalytic domain variant of the disclosure or the zinc- finger recombinase protein of the disclosure. [00212] In another aspect, the present disclosure provides a method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in a gene of a cell, the method comprising introducing into a cell a polynucleotide encoding the Gin recombinase catalytic domain variant of the disclosure or the zinc- finger recombinase protein of the disclosure. [00213] In another aspect, the present disclosure provides a method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell the zinc-finger recombinase of the disclosure or the polynucleotide encoding the zinc-finger recombinase of the disclosure. [00214] In another aspect, the present disclosure provides a method for excising a target nucleotide sequence in a chromosome of a cell, the method comprising introducing into the cell the zinc-finger recombinase of the disclosure or the polynucleotide encoding the zinc-finger recombinase of the disclosure. [00215] In some embodiments, the method of excising a target sequence from the genome of the cell comprises introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. In some embodiments, the method for excising a target sequence from the genome of the cell comprises introducing into the cell a polynucleotide encoding a zinc- finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00216] In some embodiments, the methods disclosed herein further comprise a knock down of NHEJ or inhibition of NHEJ. Exemplary methods for NHEJ knock down or inhibition include but are not limited to, a small molecule inhibitor, a zinc finger protein transcription factor (ZFP-TF), or a peptide inhibitor. In some embodiments, NHEJ is knocked-down by a small molecule. In some embodiments, NHEJ is knocked down by a small molecule inhibitor including KU0060648, VX- 984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. See, e.g., WO2018/013840. In some embodiments, the NHEJ is knocked down by the small molecule inhibitor KU0060648. In some embodiments, NHEJ is knocked down by ZFP-TFs. See, e.g., US20130253040, US20150335708, US20160296605, US9943565, US7939327, and WO2012068380. In some embodiments, NHEJ is knocked down by peptide inhibitors. In some embodiments, NHEJ is knocked-out by targeting genes including KU70, KU80, DNA-PK, XRCC4, or DNA Ligase IV using zinc finger nucleases (ZFNs), TALEN, or CRISPR/Cas systems. [00217] A zinc-finger recombinase protein of the disclosure binds the target nucleotide sequence as a dimer, interacting through the catalytic domain of the recombinase, where the DNA-binding domains of the two zinc-finger monomers may interact with distinct target nucleotide sequences. A second zinc-finger recombinase protein of the disclosure binds the donor nucleotide sequence as a dimer. A tetramer is formed between the two zinc finger recombinase dimers (the target dimer and the donor dimer), which is the active form of the recombinase capable of integrating the donor sequence into the target nucleotide sequence. In some embodiments, the two dimers comprise a Gin recombinase catalytic domain. [00218] In order for the zinc-finger recombinase protein to catalyze recombination it is necessary for the zinc finger nucleotide binding domain to recognize and bind to an appropriate DNA fragment. Typically, the DNA sequence may comprise two zinc-finger protein binding-sites recognized by the zinc finger nucleotide binding domain of the zinc-finger recombinase protein, flanking a central sequence which interacts with Gin catalytic domain. [00219] The zinc finger nucleotide binding domain is optimized for recognition of their targets. This can be done completely separately from the recombination system, using methods well known to those skilled in the art; mutagenesis followed by ‘phage display’ selection, swapping of parts from known variants of the DNA- binding domain, etc. (Pabo et al., Annu Rev Biochem.2001; 70:313-40). [00220] The methods and compositions disclosed herein can be used in any type of cell including a eukaryotic or prokaryotic cell and/or cell line. Examples of cells include, but are not limited to, prokaryotic cells, fungal cells, Archaeal cells, plant cells, insect cells, animal cells, vertebrate cells, mammalian cells and human cells. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the mammalian cell is a stem cell. In some embodiments, the eukaryotic cell is a human cell. In some embodiments, the eukaryotic cell is a plant cell. Non-limiting examples of eukaryotic cells or cell lines generated from such cells include T-cells, COS, K562, CHO (e.g., CHO-S, CHO-K1, CHO-DG44, CHO-DUXB11, CHO-DUKX, CHOK1SV), VERO, MDCK, WI38, V79, B14AF28-G3, BHK, HaK, NS0, SP2/0-Ag14, HeLa, HEK293 (e.g., HEK293-F, HEK293-H, HEK293-T), primary human hepatocyte (PHH), and perC6 cells as well as insect cells such as Spodoptera fugiperda (Sf), or fungal cells such as Saccharomyces, Pichia and Schizosaccharomyces. Examples of stem cells include, but are not limited to, embryonic stem cells, induced pluripotent stem cells (iPS cells), hematopoietic stem cells, neuronal stem cells and mesenchymal stem cells. [00221] In some embodiments, any of the methods for modifying the genome of a cell, the method for integrating an exogenous nucleotide sequence or the method for deleting (excising) a target nucleotide sequence described herein is independent of the Fis enhancer system. [00222] In some embodiments, in order to introduce the zinc finger recombinase protein into the cell, the polynucleotide encoding the zinc-finger recombinase protein is incorporated into a plasmid, a viral vector, a mini-circle or a linear DNA form. [00223] In some embodiments of the methods disclosed herein, the zinc finger nucleotide binding domain comprises the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10. [00224] In some embodiments of the method for integrating an exogenous sequence into a target sequence or for deleting a target nucleotide sequence, the target nucleotide sequence comprises the sequence set forth in SEQ ID NO: 15. [00225] In some embodiments, the target nucleotide sequence is an endogenous locus. In some embodiments, the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), and a safe-harbor locus. In some embodiments, the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. [00226] In some embodiments, the disclosure provides for the integration of an exogenous nucleic acid sequence into a safe harbor locus in the genome of a cell. A safe harbor locus is typically a genomic locus where transgenes can integrate and function in a predictable manner without perturbing endogenous gene activity. Exemplary safe harbor loci in the human genome include, without limitation the Rosa26 locus, the AAVS1 locus, and the safe harbor loci listed in Sadelain et al. Nat Rev Cancer.2012;12(1):51-8. In some embodiments, the safe harbor locus is located in chromosome 1. [00227] The mechanism of targeted integration of an exogenous nucleotide sequence into a target nucleotide sequence is the following: (a) A first zinc finger recombinase forms a dimer by recognizing the target nucleotide sequence; (b) A second zinc finger recombinase forms a dimer by recognizing the donor nucleotide sequence (the exogenous nucleotide sequence); (c) A tetramer is formed between the first and second zinc finger recombinase dimers (the target dimer and the donor dimer); (d) The two recombinase dimers rotate around the tetramer interface, which permits the strand exchange while each recombinase dimer stays covalently linked to the DNA; and (e) Religation of the nucleotide fragments, which results in strand exchange and introduction of an exogenous nucleotide sequence (the donor nucleotide sequence) into the target sequence. [00228] The mechanism of targeted excision of an endogenous nucleotide sequence is the following: (a) A first zinc finger recombinase forms a dimer by recognizing a first target nucleotide sequence flanking a first end of a nucleotide sequence to be excised; (b) A second zinc finger recombinase forms a dimer by recognizing a second target nucleotide sequence flanking a second end of a nucleotide sequence to be excised (the first and second target nucleotide sequences may or may not be identical); (c) A tetramer is formed between the first and second zinc finger recombinase dimers; (d) The two recombinase dimers rotate around the tetramer interface, which permits DNA strand exchange while each recombinase dimer stays covalently linked to the DNA; (e) Excision of the endogenous nucleotide sequence located between the first and second target nucleotide sequence; and (f) Ligation of the endogenous nucleotide sequences flanking the excised target nucleotide sequence and restoration of chromosomal DNA sequence. [00229] In some embodiments, each zinc-finger recombinase dimer is independently a homodimer. In some embodiment, each zinc-finger recombinase dimer is independently a heterodimer. In some embodiments, the tetrameric zinc finger recombinase is a homotetramer. In other embodiments, the tetrameric zinc- finger recombinase is a heterotetramer. [00230] In some embodiments, each of the two recombinase dimers comprise a gamma Gin recombinase catalytic domain. In some embodiments, one of the two recombinase dimers comprise a gamma Gin recombinase catalytic domain. [00231] The zinc finger recombinase protein or the polynucleotide encoding the zinc finger recombinase protein may be delivered to isolated cells (which in turn may be administered to a living subject for ex vivo cell therapy) or to a living subject. Delivery of gene editing molecules to cells and subjects are known in the art. Methods of delivering zinc finger recombinase proteins as described herein are described, for example, in U.S. Patent Nos.6,453,242; 6,503,717; 6,534,261; 6,599,692; 6,607,882; 6,689,558; 6,824,978; 6,933,113; 6,979,539; 7,013,219; and 7,163,824, the disclosures of all of which are incorporated by reference herein in their entireties. [00232] Suitable cells include, but are not limited to, eukaryotic and prokaryotic cells and/or cell lines. Non-limiting examples of eukaryotic cells or cell lines generated from such cells include T-cells, COS, K562, CHO (e.g., CHO-S, CHO-K1, CHO-DG44, CHO-DUXB11, CHO-DUKX, CHOK1SV), VERO, MDCK, WI38, V79, B14AF28-G3, BHK, HaK, NS0, SP2/0-Ag14, HeLa, HEK293 (e.g., HEK293-F, HEK293-H, HEK293-T), and perC6 cells as well as insect cells such as Spodoptera fugiperda (Sf), or fungal cells such as Saccharomyces, Pichia and Schizosaccharomyces. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a stem cell, such as, by way of example, embryonic stem cells, induced pluripotent stem cells (iPS cells), hematopoietic stem cells, neuronal stem cells and mesenchymal stem cells. [00233] The polynucleotide encoding the zinc finger recombinase protein, as described herein, may also be delivered using vectors containing sequences encoding one or more of the components of the zinc finger recombinase protein. In some embodiments, additional nucleic acids (e.g., donor sequences) also may be delivered via these vectors. Furthermore, it will be apparent that any of these vectors may comprise one or more DNA-binding protein-encoding sequences and/or additional nucleic acids as appropriate. Thus, when one or more zinc finger recombinase protein as described herein are introduced into the cell, and additional DNAs as appropriate, they may be carried on the same vector or on different vectors. When multiple vectors are used, each vector may comprise a sequence encoding one or multiple zinc finger recombinase proteins and additional nucleic acids as desired. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids encoding engineered DNA-binding proteins in cells (e.g., in mammalian cells) and target tissues and to co-introduce additional nucleotide sequences as desired. Such methods can also be used to administer nucleic acids to cells in vitro. In certain embodiments, nucleic acids are administered for in vivo or ex vivo gene therapy uses. [00234] Gene therapy vectors comprising the polynucleotide encoding the zinc finger recombinase protein of the disclosure can be delivered in vivo by administration to an individual patient (subject), typically by systemic administration (e.g., intravenous, intraperitoneal, intramuscular, subdermal, or intracranial infusion) or topical application, as described below. Alternatively, vectors can be delivered to cells ex vivo, such as cells explanted from an individual patient (e.g., lymphocytes, bone marrow aspirates, tissue biopsy) or universal donor hematopoietic stem cells, followed by re-implantation of the cells into a patient, usually after selection for cells which have incorporated the vector. [00235] Ex vivo cell transfection for diagnostics, research, transplant or for gene therapy (e.g., via re-infusion of the transfected cells into the host organism) is well known to those of skill in the art. In some embodiments, cells are isolated from the subject organism, transfected with a polynucleotide encoding the zinc finger recombinase protein, and re-infused back into the subject organism (e.g., patient). Various cell types suitable for ex vivo transfection are well known to those of skill in the art (see, e.g., Freshney, et al., Culture of Animal Cells, A Manual of Basic Technique (3rd ed.1994)) and the references cited therein for a discussion of how to isolate and culture cells from patients). [00236] In one embodiment, stem cells are used in ex vivo procedures for cell transfection and gene therapy. The advantage to using stem cells is that they can be differentiated into other cell types in vitro, or can be introduced into a mammal (such as the donor of the cells) where they will engraft in the bone marrow. Methods for differentiating CD34+ cells in vitro into clinically important immune cell types using cytokines such a GM-CSF, IFN-γ and TNF-α are known (see Inaba, et al. (1992) J. Exp. Med.176:1693-1702). Methods of treating a disorder in a subject or method for correcting a disease-causing mutation [00237] In one aspect, the disclosure provides a method for treating a disease disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the Gin recombinase catalytic domain variant of the disclosure or the zinc-finger recombinase protein of the disclosure. [00238] In another aspect, the disclosure provides a method for treating a disease or disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell a polynucleotide encoding the Gin recombinase catalytic domain variant of the disclosure or the zinc-finger recombinase protein of the disclosure. [00239] In another aspect, the disclosure provides a method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc-finger recombinase of the disclosure. [00240] In another aspect, the disclosure provides a method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell the polynucleotide encoding a zinc-finger recombinase of the disclosure. [00241] In some embodiments, the method for treating a disorder in a subject, comprises excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. In some embodiments, the method for treating a disorder in a subject, comprises excising a target sequence from the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00242] In another aspect, the disclosure provides a method for correcting a disease- or disorder-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the Gin recombinase catalytic domain variant of the disclosure or the zinc finger recombinase protein of the disclosure. [00243] In another aspect, the disclosure provides a method for correcting a disease- or disorder-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell a polynucleotide encoding the Gin recombinase catalytic domain variant of the disclosure or the zinc finger recombinase protein of the disclosure. [00244] In another aspect, the disclosure provides a method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc- finger recombinase of the disclosure. [00245] In another aspect, the disclosure provides a method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence in the genome of the cell by introducing into the cell the polynucleotide encoding a zinc-finger recombinase of the disclosure. [00246] In some embodiments, the method for correcting a disease-causing mutation in the genome of a cell, comprises excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. In some embodiments, the method for treating a disorder in a subject, comprises excising a target sequence from the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00247] In some embodiments, the method for treating a disorder in a subject or method for correcting a disease-causing mutation in the genome of a cell disclosed herein further comprise a knock down of NHEJ or inhibition of NHEJ. Exemplary methods for NHEJ knock down or inhibition include but are not limited to, a small molecule inhibitor, a zinc finger protein transcription factor (ZFP-TF), or a peptide inhibitor. In some embodiments, NHEJ is knocked-down by a small molecule. In some embodiments, NHEJ is knocked down by a small molecule inhibitor including KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. In some embodiments, the NHEJ is knocked down by the small molecule inhibitor KU0060648. In some embodiments, NHEJ is knocked down by ZFP-TFs. In some embodiments, NHEJ is knocked down by peptide inhibitors. In some embodiments, NHEJ is knocked-out by targeting genes including KU70, KU80, DNA-PK, XRCC4, or DNA Ligase IV using zinc finger nucleases (ZFNs), TALEN, or CRISPR/Cas systems. [00248] In one embodiment of the method for treating a disease or disorder or for correcting a disease-causing mutation, at least one cell, cell type or tissue comprise a recombination site that is recognized by a zinc finger nucleotide binding domain. This cell(s) is transformed with a donor nucleic acid construct (a “donor construct”) comprising a second recombination sequence and one or more polynucleotides of interest (typically a therapeutic gene). Into the same cell, a zinc finger recombinase protein of the disclosure or a polynucleotide encoding the zinc finger recombinase protein of the disclosure is introduced. The zinc finger recombinase protein specifically recognizes the recombination sequences forming a tetramer, under conditions such that the nucleic acid sequence of interest is inserted into the genome via a recombination event between the first and second recombination sites. Subjects treatable using the methods of the invention include both humans and non-human animals. [00249] A variety of diseases or disorders may be treated by employing the methods of the disclosure. Non-limiting examples include monogenic disorders, infectious diseases, acquired disorders, cancer, and the like. Exemplary monogenic disorders include ADA deficiency, cystic fibrosis, familial-hypercholesterolemia, hemophilia, chronic granulomatous disease, Duchenne muscular dystrophy, Fanconi anemia, sickle-cell anemia, Gaucher's disease, Hunter syndrome, X-linked SCID, and the like. [00250] Genetic disease or disorders may also be treated or prevented using the methods disclosed herein. Exemplary genetic diseases that may be treated and/or prevented by zinc finger recombinase protein and methods described herein include, but are not limited to, achondroplasia, achromatopsia, acid maltase deficiency, adenosine deaminase deficiency (OMIM No.102700), adrenoleukodystrophy, aicardi syndrome, alpha-1 antitrypsin deficiency, alpha-thalassemia, androgen insensitivity syndrome, apert syndrome, arrhythmogenic right ventricular, dysplasia, ataxia telangiectasia, barth syndrome, beta-thalassemia, blue rubber bleb nevus syndrome, canavan disease, chronic granulomatous diseases (CGD), cri du chat syndrome, cystic fibrosis, dercum's disease, ectodermal dysplasia, fanconi anemia, fibrodysplasia ossificans progressive, fragile X syndrome, galactosemis, Gaucher’s disease, generalized gangliosidoses (e.g., GM1), hemochromatosis, the hemoglobin C mutation in the 6th codon of beta-globin (HbC), hemophilia, Huntington’s disease, Hurler Syndrome, hypophosphatasia, Klinefelter syndrome, Krabbes Disease, Langer- Giedion Syndrome, leukocyte adhesion deficiency (LAD, OMIM No.116920), leukodystrophy, long QT syndrome, Marfan syndrome, Moebius syndrome, mucopolysaccharidosis (MPS), nail patella syndrome, nephrogenic diabetes insipdius, neurofibromatosis, Neimann-Pick disease, osteogenesis imperfecta, phenylketonuria (PKU). porphyria, Prader-Willi syndrome, progeria, Proteus syndrome, retinoblastoma, Rett syndrome, Rubinstein-Taybi syndrome, Sanfilippo syndrome, severe combined immunodeficiency (SCID), Shwachman syndrome, sickle cell disease (sickle cell anemia), Smith-Magenis syndrome, Stickler syndrome, Tay-Sachs disease, Thrombocytopenia Absent Radius (TAR) syndrome, Treacher Collins syndrome, trisomy, tuberous sclerosis, Turner’s syndrome, urea cycle disorder, von Hippel-Landau disease, Waardenburg syndrome, Williams syndrome, Wilson’s disease, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome (XLP, OMIM No.308240), Charcot Marie Tooth (CMT) disease, Autosomal dominant polycystic kidney disease (ADPKD), and the like. [00251] The methods disclosed herein also allow for treatment of infections (viral or bacterial) in a host (e.g., by blocking expression of viral or bacterial receptors, thereby preventing infection and/or spread in a host organism). Non- limiting examples of viruses or viral receptors that may be targeted include herpes simplex virus (HSV), such as HSV-1 and HSV-2, varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV), HHV6 and HHV7. The hepatitis family of viruses includes hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the delta hepatitis virus (HDV), hepatitis E virus (HEV) and hepatitis G virus (HGV). Other viruses or their receptors may be targeted, including, but not limited to, Picornaviridae (e.g., polioviruses, etc.); Caliciviridae; Togaviridae (e.g., rubella virus, dengue virus, etc.); Flaviviridae; Coronaviridae; Reoviridae; Birnaviridae; Rhabodoviridae (e.g., rabies virus, etc.); Filoviridae; Paramyxoviridae (e.g., mumps virus, measles virus, respiratory syncytial virus, etc.); Orthomyxoviridae (e.g., influenza virus types A, B and C, etc.); Bunyaviridae; Arenaviridae; Retroviradae; lentiviruses (e.g., HTLV-I; HTLV-II; HIV-1 (also known as HTLV-III, LAV, ARV, hTLR, etc.) HIV-II); simian immunodeficiency virus (SIV), human papillomavirus (HPV), influenza virus and the tick-borne encephalitis viruses. See, e.g. Virology, 3rd Edition (W. K. Joklik ed.1988); Fundamental Virology, 2nd Edition (B. N. Fields and D. M. Knipe, eds.1991), for a description of these and other viruses. Also included are infections with other pathogenic organisms such as Mycobacterium Tuberculosis, Mycoplasma pneumoniae, and the like or parasites such as Plasmodium falciparum, and the like. [00252] The method for treatment or correction of a disease-causing mutation can take place in vivo or ex vivo. By “in vivo” it is meant in the living body of an animal. By “ex vivo” it is meant that cells or organs are modified outside of the body, such cells or organs are typically returned to a living body. [00253] Methods for the therapeutic administration of vectors or constructs including the zinc finger recombinase proteins of the disclosure are well known in the art. Nucleic acid constructs can be delivered with cationic lipids (Goddard, et al, Gene Therapy, 4:1231-1236, 1997; Gorman, et al, Gene Therapy 4:983-992, 1997; Chadwick, et al, Gene Therapy 4:937-942, 1997; Gokhale, et al, Gene Therapy 4:1289-1299, 1997; Gao, and Huang, Gene Therapy 2:710-722, 1995, all of which are incorporated by reference herein), using viral vectors (Monahan, et al, Gene Therapy 4:40-49, 1997; Onodera, et al, Blood 91:30-36, 1998, all of which are incorporated by reference herein), by uptake of “naked DNA”, and the like. Techniques well known in the art for the transfection of cells (see discussion above) can be used for the ex vivo administration of nucleic acid constructs. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1 pl). [00254] As described herein, the zinc finger recombinase protein and methods described herein can be used for genome modification, genome correction, and genome disruption. [00255] The zinc finger recombinase protein and methods described herein can also be applied to stem cell based therapies, including but not limited to editing that results in: correction of somatic cell mutations; disruption of dominant negative alleles; disruption of the genome required for the entry or productive infection of pathogens into cells; enhanced tissue engineering, for example, by editing genome activity to promote the differentiation or formation of functional tissues; and/or disrupting genome activity to promote the differentiation or formation of functional tissues; blocking or inducing differentiation, for example, by editing the genes that block differentiation to promote stem cells to differentiate down a specific lineage pathway. Cell types for this procedure include but are not limited to, T-cells, B cells, hematopoietic stem cells, and embryonic stem cells. Additionally, induced pluripotent stem cells (iPSC) may be used which would also be generated from a patient’s own somatic cells. Therefore, these stem cells or their derivatives (differentiated cell types or tissues) could be potentially engrafted into any person regardless of their origin or histocompatibility. [00256] As noted above, the zinc finger recombinase protein and methods described herein can be used for gene modification, gene correction, and gene disruption. [00257] The zinc finger recombinase protein and methods described herein can also be applied to stem cell based therapies, including but not limited to editing that results in: correction of somatic cell mutations; disruption of dominant negative alleles; disruption of genes required for the entry or productive infection of pathogens into cells; enhanced tissue engineering, for example, by editing gene activity to promote the differentiation or formation of functional tissues; and/or disrupting gene activity to promote the differentiation or formation of functional tissues; blocking or inducing differentiation, for example, by editing genes that block differentiation to promote stem cells to differentiate down a specific lineage pathway. Cell types for this procedure include but are not limited to, T-cells, B cells, hematopoietic stem cells, and embryonic stem cells. Additionally, induced pluripotent stem cells (iPSC) may be used which would also be generated from a patient’s own somatic cells. Therefore, these stem cells or their derivatives (differentiated cell types or tissues) could be potentially engrafted into any person regardless of their origin or histocompatibility. [00258] In addition to therapeutic applications, the zinc finger recombinase protein and methods described herein can be used for cell line engineering and the construction of disease models. EXAMPLES Example 1: Zinc finger recombinase protein design [00259] A Gin recombinase catalytic domain (including (i) H106Y mutation (SEQ ID NO: 2); (ii) F104N mutation (SEQ ID NO: 3) and (iii) no modifications (SEQ ID NO: 1)) was each independently fused to the N-terminus of a zinc finger DNA binding domain using the linker KSGTG (SEQ ID NO: 8). A Gin core sequence scoring algorithm was used to identify Gin core sequences in the HPRT gene, as well as safe harbor site on chromosome 1. [00260] The left (SEQ ID NO: 9) and right (SEQ ID NO: 10) arms of the zinc finger nucleotide binding domain were designed to target a sequence from the HPRT gene. [00261] The zinc finger nucleotide binding domains or ZFPs were designed to target the sequences flanking the Gin core sequences. The Gin recombinase catalytic domain was selected to target the Gin core sequence. For HPRT target site, the Gin core sequence was SEQ ID NO: 12. For the safe harbor site on chromosome 1 target site, the Gin core sequence was SEQ ID NO: 27 (CTAATTACCTTCATTATAGT) and SEQ ID NO: 28 (ACAAATAGTATAATTTGAGT). [00262] Gamma Gin recombinase catalytic domains were codon-optimized for humans, synthesized as gBlocks and cloned into a mammalian expression vector pVax. Gin variants mutations at position H106Y (protein sequence - SEQ ID NO: 2) or F104N (protein sequence - SEQ ID NO: 3) were generated using the NEB ® site- directed mutagenesis kit according to the manufacturer’s instructions and using the starting codon-optimized Gamma Gin recombinase catalytic domains as a template. Gin variant sequences were confirmed via Sanger sequencing. [00263] Zinc finger DNA binding domains capable of binding HPRT gene were assembled and cloned into the Gin expression vector. Clones sequences were confirmed via Sanger sequencing. [00264] The full pVAX plasmid DNA sequence of the left arm of the zinc finger recombinase protein comprising F104N mutation is SEQ ID NO: 16 and the full plasmid DNA sequence of the right arm of the zinc finger recombinase protein comprising F104N mutation is SEQ ID NO: 17. Example 2: Donor construct design [00265] Site specific donor molecules were cloned by inserting the zinc finger recombinase sites (ZFP binding site: Gin core sequence: ZFP binding site) into a pUC19 vector backbone. The donor construct was generated using HiFi Assembly kit (NEB ® ). The donor fragment was synthesized by IDT ® and provided as gene fragments (gBlock), including HiFi assembly overhangs. The donor construct comprised the binding sites of the two zinc finger nucleotide binding domains flanking the Gin core sequence (ZFP binding site-Gin core sequence-ZFP binding site). [00266] The pUC19 vector backbone was PCR amplified. The gBlock and primer sequences are shown below. [00267] Additional sequence information (including one of the genomic primer binding sites) was added to support a Standard Next Generation sequencing (NGS)- based Target Integration (TI) assay. A unique tag sequence was added to differentiate between wildtype zinc finger recombinase protein (SEQ ID NO: 23 - TGTATTTGC) and target-integrated (TI) PCR amplicons (SEQ ID NO: 24 - GCTTTATTG). Recombinase-mediated TI events resulted in reads with the TI tag. Example 3: Targeted integration in human K562 cells [00268] K562 (ATCC ® CCL243 TM ) cells were obtained from ATCC and were maintained in RPMI1640 medium with 10% FBS and 1x PSG at 37°C with 5% CO 2 atmosphere. [00269] Various doses of plasmid DNA encoding the zinc finger recombinase protein (H106Y variant or F104N variant) with or without the donor molecule (also supplied as pDNA) were electroporated into K562 cells using the SF cell line 96-well Nucleofector TM kit (Lonza ® , V4SC-2960) following the manufacturer’s instructions. [00270] In brief, cells were washed once with 1x PBS (divalent cation-free) and resuspended at 2x10 5 cells per 13 µl of supplemented SF cell line 96-well Nucleofector TM solution. For each transfection, 13 µl of the cell suspension was mixed with 7 µl of pDNA and transferred to the Lonza ® Nucleocuvette TM plate and electroporated using the protocol for K562 cells (Nucleofector TM program 96-FF-120) on an Amaxa Nucleofector TM 96-well Shuttle System (Lonza ® ). Electroporated cells were incubated at room temperature for 10 min and then transferred to 180 µl of prewarmed complete medium in a 96-well tissue culture plate. Cells were incubated for 72 h and then harvested for targeted integration quantification. Genomic DNA was extracted using QuickExtract TM following the manufacturer’s instructions. Cells were subjected to an optional cold shock at 30°C overnight before transferring them to 37°C. Example 4: Standard NGS-based Targeted Integration assay [00271] PCR primers for loci of interest were designed using Primer3 design tool with the following optimal conditions: amplicon size of 200-nt; a melting temperature of 60°C; primer lengths of 20-nt; and GC content of 50%. Adaptors were added for a second PCR reaction to add the Illumina library sequences (forward primer: ACACGACGCTCTTCCGATCT (SEQ ID NO: 25); reverse primer: GACGTGTGCTCTTCCGAT (SEQ ID NO: 26)). The HPRT locus specific primer sequences used were: SEQ ID NO: 29 (taaaacgacggccagtgaattc) and SEQ ID NO: 30 (tctgctaatggagctatgcaat). [00272] Regions of interest were amplified in 25 µl using 2.5 µl of genomic DNA from the QuickExtract TM gDNA solution with AccuPrime HiFi Polymerase (Invitrogen ® ). Primers were used at a final concentration of 0.1 µM with the following thermocycling conditions: initial melt of 95°C for 5 min; 30 cycles of 95°C for 30s, 55°C for 30s and 68°C for 40x; and a final extension at 68°C for 10 min. [00273] One microliter of this PCR product was used in a 20 µl PCR reaction to add the Illumina library sequences with Phusion TM High-Fidelity PCR MasterMix with HF Buffer (NEB ® ). Primers were used at a final concentration of 0.5 µM with the following thermocycling conditions: initial melt of 98°C for 30 s, 12 cycles for 98°C for 10 s, 60°C for 30 s and 72°C for 40 s; and a final extension at 72°C for 10 min. [00274] PCR libraries were purified using the QIAquick TM PCR purification kit (Qiagen). Samples were quantified with the Qubit TM dsDNA HS Assay kit (Invitrogen ® ) and diluted to 2 nM. [00275] The libraries were then run according to the manufacturer’s instructions on either an Illumina ® MiSeq TM using a standard 300-cycle kit or an Illumina ® NextSeq 500 using a mid-output 300-cycle kit.TI efficiency was determined by quantifying the total number of wild-type reads and the total number of TI reads (including the unique TI sequence tag). See Figure 1, which shows a graph comparing the target integration efficiency of H106Y zinc finger recombinase variant and F104N zinc finger recombinase variant. The target integration efficiency of the F104N zinc finger recombinase variant is around 20%, while the target integration efficiency of the H106Y zinc finger recombinase variant is around 1.5%. Example 5: Flow cytometry assay [00276] A GFP expression cassette was cloned into the donor vector backbone described above. Transfections were performed as described and cells were maintained for 3 weeks. After 3 weeks, unincorporated donor molecules had been washed out and only stably integrated donor molecules resulted in GFP expression. [00277] 1x10 6 K562 cells were washed in PBS, resuspended in 200 µl FACS buffer (Ca2+/Mg2+ free PBS, 1% BSA) and subjected to GFP quantification via flow cytometry assay, where the transfection efficiency was determined. [00278] Flow cytometry was performed on an Invitrogen ® Attune NxT flow cytometer following the manufacturer’s instructions. The percentage of GFP expressing cells was compared between non-transfected cells showing background signal (Fig.2, Panel A), cells transfected only with the donor molecule showing random GFP integration (Fig.2, Panel B) and cells transfected with the F104N Zinc Finger recombinase variant together with the donor construct (Fig.2, Panel C). As shown in Figure 2, the GFP fluorescence detected in cells transfected with F104N Zinc Finger recombinase variant and HPRT donor construct is much higher than the fluorescence detected in cells transfected with the donor only (17.7% vs 2.91%). Example 6: Zinc finger nuclease design [00279] Zinc finger proteins targeted to HPRT were designed and incorporated into plasmids as described elsewhere. Table A shows the recognition helices within the DNA binding domains of two exemplary HPRT ZFNs (N>C finger sequence). Table B shows the target sites for these ZFNs (DNA target sites indicated in uppercase letters; non-contacted nucleotides indicated in lowercase). Table A Table B Example 7: ZFR-mediated Target Integration (TI) versus ZFN-mediated TI [00280] HPRT ZFN control (see Example 6) or HPRT ZFR constructs (F104N:I94V) were co-transfected with donor plasmids into K562 cells as described in Example 3. KU0060648, a NHEJ inhibitor at a concentration of 0 µM, 0.032 µM, 0.179 µM or 1.00 µM was added to the recovery media. Cells were harvested after 3 days for subsequent PCR-based NGS analysis as described in Example 4. As shown in Figure 4, Panel B, ZFN-induced NHEJ-mediated targeted integration in the presence of KU0060648 was negatively impacted. %Indel, %perfect TI (Indel-free TI) and %total TI all decreased as the dose of the NHEJ inhibitor increased. In contrast, the ZFR (F104N:I94V) showed an increase in both %perfect TI and %total TI increased while %Indel dropped as KU0060648 dose increased (Fig.4, Panel B). This demonstrates that the ZFR-mediated targeted integration mechanism is distinct from ZFN-induced NHEJ-mediated targeted integration. Example 8: Preparation of a stable excision reporter cell line [00281] A K562 reporter cell line with two HPRT ZFR binding sites was generated. First, an excision reporter construct was cloned into a plasmid. The sequence of the plasmid is set forth in SEQ ID NO: 81. The reporter construct has two binding sites for the HPRT ZFR, spaced 2888-nt apart. The HPRT ZFR binding site is as follows: [00282] The cloned excision construct was co-transfected with a ZFN:30035 and 30054 (which cuts both the genome and the plasmid) into K562 cells for integration into the AAVS1 safe locus site by ZFN-induced NHEJ-mediated targeted integration as previously described (see, e.g., Miller, et al., Enhancing gene editing specificity by attenuating DNA cleavage kinetics, Nature Biotechnology (vol.37, 2019)). The reporter construct comprises a polynucleotide sequence that helps facilitate the integration of the reporter construct into the AAVS1 (see Table C). A PCR-based assay was used to detect integration of the HPRT donor construct into the AAVS1 locus as described in Example 4. The primer binding site targeted to detect proper integration into AAVS1 is set forth in Table C. A clonal K562 reporter cell line was selected after proper detection of HPRT donor integration into the AAVS1 locus. Table C Example 9: ZFR (H106Y)-mediated targeted excision is enhanced with NHEJ inhibition [00283] Targeted excision was induced following transfection of the clonal K562 cell line with a H106Y ZFR, F104N ZFR or ZFN construct. The cells were treated with 0 µM or 3.14 µM KU0060648, a NHEJ inhibitor post-transfection. A PCR-based NGS assay was performed as described in Example 4. The following primers were used to detect excision events: Forward primer: NO: 80) and the reverse primer: [00284] Additional sequence information (including one of the genomic primer binding sites) was added to support a Standard Next Generation sequencing (NGS)- based Target Excision assay. A unique tag sequence was added to differentiate between a lack of ZFR excision activity (SEQ ID NO: 24 - GCTTTATTG) and detectable targeted excision (SEQ ID NO: 23 - TGTATTTGC) induced by the transfected ZFR constructs. [00285] As shown in Figure 5, Panel B, in the absence of a NHEJ inhibitor (KU0060648), ZFN and ZFR variants (H106Y and F104N) targeting the ZFR binding site efficiently excised the DNA molecule flanked by the two ZFR sites as measured by %perfect excision (Indel-free target locus after excision), % total excision (non- perfect events), and %Indels within the non-excised target sites. In the presence of 3.14 µM KU0060648, the ZFNs and F104N ZFR variant had reduced excision events, while the H106Y ZFR variant showed increased %perfect excision and %total excision with decreased %Indel. Although the hyperactive H106Y ZFR variant performed poorly in targeted integration experiments as represented in Figure 1, the outcome changed in the donor-free application of targeted excision. Therefore, inhibition of NHEJ can be beneficial for both ZFR-mediated targeted integration and ZFR-mediated targeted excision. NUMBERED EMBODIMENTS [00286] Particular embodiments of the disclosure are set forth in the following numbered paragraphs: [00287] 1. A Gin recombinase catalytic domain variant comprising a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00288] 2. The Gin recombinase catalytic domain variant according to paragraph 1, further comprising a His106Tyr amino acid substitution. [00289] 3. The Gin recombinase catalytic domain variant according to paragraph 2, comprising the amino acid sequence set forth in any one of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 56, or SEQ ID NO: 60. [00290] 4. The Gin recombinase catalytic domain variant according to paragraph 1, further comprising an Ile94Val amino acid substitution. [00291] 5. The Gin recombinase catalytic domain variant according to paragraph 4, comprising the amino acid sequence set forth in any one of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 57, or SEQ ID NO: 61. [00292] 6. A polynucleotide encoding a Gin recombinase catalytic domain variant, wherein the nucleic acid sequence encoding the Gin recombinase catalytic domain variant comprises the nucleotide sequence set forth in SEQ ID NO: 7. [00293] 7. A polynucleotide encoding a Gin recombinase catalytic domain variant according to any one of paragraphs 1-5. [00294] 8. A zinc-finger recombinase, comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a Phe104Asn amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00295] 9. The zinc finger recombinase according to paragraph 8, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution. [00296] 10. The zinc finger recombinase according to paragraph 9, wherein the Gin recombinase catalytic domain variant comprises the amino acid sequence set forth in any one of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 56, or SEQ ID NO: 60. [00297] 11. The zinc finger recombinase according to paragraph 8, wherein the Gin recombinase catalytic domain variant further comprises an Ile94Val amino acid substitution. [00298] 12. The zinc finger recombinase according to paragraph 11, wherein the Gin recombinase catalytic domain variant comprises the amino acid sequence set forth in any one of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 57, or SEQ ID NO: 61. [00299] 13. The zinc-finger recombinase according to any one of paragraphs 8- 12, wherein the zinc-finger recombinase protein is a multimeric protein. [00300] 14. The zinc-finger recombinase according to paragraph 13, wherein the zinc-finger recombinase protein is a homomultimeric protein. [00301] 15. The zinc-finger recombinase according to paragraph 13, wherein the zinc-finger recombinase protein is a heteromultimeric protein. [00302] 16. The zinc-finger recombinase according to paragraph 13, wherein said zinc-finger recombinase protein is a dimeric protein. [00303] 17. The zinc-finger recombinase according to paragraph 16, wherein said zinc-finger recombinase protein is a homodimeric protein. [00304] 18. The zinc-finger recombinase according to paragraph 16, wherein said zinc-finger recombinase protein is a heterodimeric protein. [00305] 19. The zinc-finger recombinase according to paragraph 14, wherein said zinc-finger recombinase protein is a tetrameric protein. [00306] 20. The zinc-finger recombinase according to paragraph 19, wherein said zinc-finger recombinase protein is a homotetrameric protein. [00307] 21. The zinc-finger recombinase according to paragraph 19, wherein said zinc-finger recombinase protein is a heterotetrameric protein. [00308] 22. The zinc-finger recombinase according to any one of paragraphs 8 to 21, wherein the zinc finger nucleotide binding domain comprises the sequence as set forth in SEQ ID NO: 9 or SEQ ID NO: 10. [00309] 23. The zinc-finger recombinase according to any one of paragraphs 8 to 22, wherein the zinc finger recombinase protein binds a nucleotide sequence comprising the sequence as set forth in SEQ ID NO: 15. [00310] 24. The zinc-finger recombinase according to any one of paragraphs 8 to 23, wherein the zinc finger nucleotide binding domain is capable of binding an endogenous locus. [00311] 25. The zinc-finger recombinase according to paragraph 24, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC) gene, Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. [00312] 26. A polynucleotide encoding the zinc-finger recombinase according to any one of paragraphs 8-25. [00313] 27. The polynucleotide according to paragraph 26, wherein the nucleic acid sequence encoding the Gin recombinase catalytic domain variant comprises the nucleotide sequence set forth in SEQ ID NO: 7. [00314] 28. A vector comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to paragraphs 6-7. [00315] 29. A vector comprising the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00316] 30. A cell comprising the vector according to paragraph 28 or 29. [00317] 31. A cell comprising the Gin recombinase catalytic domain variant according to any one of paragraphs 1-5. [00318] 32. A cell comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to paragraphs 6-7. [00319] 33. A cell comprising the zinc finger recombinase protein according to any of paragraphs 8-25. [00320] 34. A cell comprising the polynucleotide encoding the zinc-finger recombinase according to paragraphs 26-27. [00321] 35. The cell according to any one of paragraphs 30 to 34, wherein the cell is a eukaryotic cell. [00322] 36. The cell according to paragraph 35, wherein the cell is a mammalian cell. [00323] 37. The cell according to paragraph 36, wherein the wherein the cell is a stem cell. [00324] 38. The cell according to paragraph 35, wherein the cell is a human cell. [00325] 39. A pharmaceutical composition comprising the Gin recombinase catalytic domain variant according to any one of paragraphs 1-5; and a pharmaceutically acceptable carrier. [00326] 40. A pharmaceutical composition comprising the polynucleotide encoding the Gin recombinase catalytic domain variant according to paragraphs 6-7; and a pharmaceutically acceptable carrier. [00327] 41. A pharmaceutical composition comprising the zinc-finger recombinase according to any one of paragraphs 8 to 25; and a pharmaceutically acceptable carrier. [00328] 42. A pharmaceutical composition comprising the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27; and a pharmaceutically acceptable carrier. [00329] 43. A method for modifying the genome of a cell, the method comprising introducing into a cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00330] 44. A method for modifying the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00331] 45. A method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in genome of a cell, the method comprising introducing into a cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00332] 46. A method for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00333] 47. A method for disrupting a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00334] 48. A method for disrupting a target nucleotide sequence in the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00335] 49. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00336] 50. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00337] 51. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00338] 52. A method for excising a target nucleotide sequence from the genome of a cell, the method comprising introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00339] 53. The method according to any one of paragraphs 49-52, further comprising introducing into the cell a non-homologous end joining (NHEJ) inhibitor. [00340] 54. The method according to paragraph 53, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00341] 55. The method according to paragraph 54, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00342] 56. A method for treating a disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00343] 57. A method for treating a disorder in a subject, the method comprising modifying a target sequence in the genome of the cell by introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00344] 58. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00345] 59. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00346] 60. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00347] 61. A method for treating a disorder in a subject, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00348] 62. The method according to any one of paragraphs 58-61, further comprising administering a non-homologous end joining (NHEJ) inhibitor. [00349] 63. The method according to paragraph 62, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00350] 64. The method according to paragraph 63, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00351] 65. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell comprising introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00352] 66. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising modifying a target sequence in the genome of the cell comprising introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00353] 67. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence from the genome of the cell by introducing into the cell the zinc-finger recombinase according to any one of paragraphs 8-25. [00354] 68. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence in the genome of the cell by introducing into the cell the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27. [00355] 69. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence from the genome of the cell by introducing into the cell a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00356] 70. A method for correcting a disease-causing mutation in the genome of a cell, the method comprising excising a target sequence in the genome of the cell by introducing into the cell a polynucleotide encoding a zinc-finger recombinase comprising a Gin recombinase catalytic domain variant operatively linked to a zinc- finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00357] 71. The method according to any one of paragraphs 67-70, wherein the method further comprises a non-homologous end joining (NHEJ) inhibitor. [00358] 72. The method according to paragraph 71, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00359] 73. The method according to paragraph 72, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00360] 74. The method according to any one of paragraphs 43 to 73, wherein the cell is a eukaryotic cell. [00361] 75. The method according to paragraph 74, wherein the cell is a mammalian cell. [00362] 76. The method according to paragraph 75, wherein the cell is a stem cell. [00363] 77. The method according to paragraph 74, wherein the cell is a human cell. [00364] 78. The method according to any one of paragraphs 43 to 73, wherein the method is independent of Fis. [00365] 79. The method according to any one of paragraphs 43 to 78, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. [00366] 80. The method according to any one of paragraphs 45 to 78, wherein the target nucleotide sequence is an endogenous locus. [00367] 81. The method according to paragraph 80, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. [00368] 82. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in modifying the genome of a cell. [00369] 83. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in modifying the genome of a cell. [00370] 84. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. [00371] 85. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. [00372] 86. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in disrupting a target nucleotide sequence in the genome of a cell. [00373] 87. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in disrupting a target nucleotide sequence in the genome of a cell. [00374] 88. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in excising a target nucleotide sequence from the genome of a cell. [00375] 89. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in excising a target nucleotide sequence from the genome of a cell. [00376] 90. A zinc finger recombinase for use in excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00377] 91. A polynucleotide encoding a zinc-finger recombinase for use in excising a target nucleotide sequence from the genome of a cell, wherein the zinc- finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00378] 92. The zinc finger recombinase for use according to paragraph 88 or 90 or polynucleotide encoding a zinc finger recombinase according to paragraph 89 or 91, further comprising the use of a non-homologous end joining (NHEJ) inhibitor. [00379] 93. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 92, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00380] 94. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 93, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00381] 95. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in treating a disorder in a subject by modifying a target sequence in the genome of the cell. [00382] 96. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in treating a disorder in a subject by modifying a target sequence in the genome of the cell. [00383] 97. The zinc-finger recombinase according to any one of paragraphs 8- 25 for use in treating a disorder in a subject by excising a target sequence from the genome of the cell. [00384] 98. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in treating a disorder in a subject, by excising a target sequence from the genome of the cell. [00385] 99. A zinc-finger recombinase for use in treating a disorder in a subject, by excising a target sequence from the genome of a cell, wherein the zinc- finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00386] 100. A polynucleotide encoding a zinc-finger recombinase for use in treating a disorder in a subject, by excising a target sequence from the genome of a cell , wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00387] 101. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 97-100, for use with a non-homologous end joining (NHEJ) inhibitor. [00388] 102. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 101, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00389] 103. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 102, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00390] 104. The zinc-finger recombinase according to any one of paragraphs 8-25 for use in correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. [00391] 105. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. [00392] 106. The zinc-finger recombinase according to any one of paragraphs 8-25 for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell. [00393] 107. The polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 for use in correcting a disease-causing mutation in the genome of a cell. [00394] 108. A zinc finger recombinase for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00395] 109. A polynucleotide encoding a zinc-finger recombinase for use in correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00396] 110. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 106-109, for use with a non-homologous end joining (NHEJ) inhibitor. [00397] 111. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 110, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00398] 112. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 111, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00399] 113. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 82-112, wherein the cell is a eukaryotic cell. [00400] 114. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 113, wherein the cell is a mammalian cell. [00401] 115. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 114, wherein the cell is a stem cell. [00402] 116. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 113, wherein the cell is a human cell. [00403] 117. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 82-116, wherein the use is independent of Fis. [00404] 118. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 82-117, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. [00405] 119. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to any one of paragraphs 84-118, wherein the target nucleotide sequence is an endogenous locus. [00406] 120. The zinc finger recombinase or polynucleotide encoding a zinc finger recombinase for use according to paragraph 119, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. [00407] 121. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for modifying the genome of a cell. [00408] 122. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for modifying the genome of a cell. [00409] 123. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. [00410] 124. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for integrating an exogenous nucleotide sequence into a target nucleotide sequence in the genome of a cell. [00411] 125. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for disrupting a target nucleotide sequence in the genome of a cell. [00412] 126. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for disrupting a target nucleotide sequence in the genome of a cell. [00413] 127. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell. [00414] 128. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell. [00415] 129. Use of a zinc finger recombinase in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00416] 130. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for excising a target nucleotide sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of sequences SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00417] 131. The use according to any one of paragraphs 127-130, further comprising the use of a non-homologous end joining (NHEJ) inhibitor. [00418] 132. The use according to paragraph 131, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00419] 133. The use according to paragraph 132, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00420] 134. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for treating a disorder in a subject by modifying a target sequence in the genome of the cell. [00421] 135. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for treating a disorder in a subject by modifying a target sequence in the genome of the cell. [00422] 136. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for treating a disorder in a subject by excising a target sequence from the genome of the cell. [00423] 137. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of the cell. [00424] 138. Use of a zinc-finger recombinase in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of a cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00425] 139. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for treating a disorder in a subject, by excising a target sequence from the genome of a cell wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00426] 140. The use according to any one of paragraphs 136-139, for use with a non-homologous end joining (NHEJ) inhibitor. [00427] 141. The use according to paragraph 140, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00428] 142. The use according to paragraph 141, wherein the small molecule inhibitor is selected from the group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00429] 143. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. [00430] 144. Use of a polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by modifying a target sequence in the genome of the cell. [00431] 145. Use of the zinc-finger recombinase according to any one of paragraphs 8-25 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell. [00432] 146. Use of the polynucleotide encoding a zinc-finger recombinase according to paragraph 26 or 27 in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell. [00433] 147. Use of a zinc finger recombinase in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc-finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00434] 148. Use of a polynucleotide encoding a zinc-finger recombinase in the preparation of a medicament for correcting a disease-causing mutation in the genome of a cell by excising a target sequence from the genome of the cell, wherein the zinc- finger recombinase comprises a Gin recombinase catalytic domain variant operatively linked to a zinc-finger nucleotide binding domain, wherein the Gin recombinase catalytic domain variant further comprises a His106Tyr amino acid substitution with reference to a Gin recombinase catalytic domain amino acid sequence as set forth in any one of SEQ ID NO: 1, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 35. [00435] 149. The use according to any one of paragraphs 145-148, for use with a non-homologous end joining (NHEJ) inhibitor. [00436] 150. The use according to paragraph 149, wherein the NHEJ inhibitor is selected from the group consisting of a small molecule inhibitor, a zinc-finger protein transcription factor (ZFP-TF), and a peptide inhibitor. [00437] 151. The use according to paragraph 150, wherein the small molecule inhibitor is selected from a group consisting of KU0060648, VX-984, W7, Chlorpromazine, Vanillin, Nu7026, Nu7441, Mirin, SCR7, AG14361, M9831 and VXc-296. [00438] 152. The use according to any one of paragraphs 121-151, wherein the cell is a eukaryotic cell. [00439] 153. The use according to paragraph 152, wherein the cell is a mammalian cell. [00440] 154. The use according to paragraph 153, wherein the cell is a stem cell. [00441] 155. The use according to paragraph 152, wherein the cell is a human cell. [00442] 156. The use according to any one of paragraphs 121-155, wherein the use is independent of Fis. [00443] 157. The use according to any one of paragraphs 121-156, wherein the polynucleotide encoding the zinc-finger recombinase is introduced into the cell using a plasmid, a viral vector, a mini-circle or a linear DNA form. [00444] 158. The use according to any one of paragraphs 123-157, wherein the target nucleotide sequence is an endogenous locus. [00445] 159. The use according to paragraph 158, wherein the endogenous locus is selected from the group consisting of Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene, T Cell Receptor Alpha Constant (TRAC), Adeno-Associated Virus Integration Site 1 (AAVS1) and a safe-harbor locus. [00446] Although disclosure has been provided in some detail by way of illustration and example for the purposes of clarity of understanding, it will be apparent to those skilled in the art that various changes and modifications can be practiced without departing from the spirit or scope of the disclosure. Accordingly, the foregoing descriptions and examples should not be construed as limiting.
Next Patent: PRODRUG COMPOSITIONS AND METHODS OF TREATMENT