Nova Patents
IL284741A

Gene therapy for retinitis pigmentosa

Abstract

This record has no abstract on file.

IL284741A, drawing sheet 1
Sheet 1 of 28

Term

No projected expiry on record.

  1. Priority
  2. Filed
  3. Published
  4. Today

130 claims: 86 independent, 44 dependent

  1. 1
    A method for treating retinitis pigmentosa in a mammal, comprising administering to the eye of the mammal a recombinant adeno-associated virus (rAAV) viral particle comprising a rAAV vector comprising nucleic acid encoding a miR-708.
  2. 2
    A method for treating endoplasmic reticulum (ER) stress in a cell of a mammal, comprising administering to the mammal a rAAV viral particle comprising a rAAV vector comprising nucleic acid encoding a miR-708.
  3. 4
    The method claim 2 or 3, wherein the cell is an ocular cell.
  4. 7
    The method of any one of claims 1-6, wherein the method comprises reducing one or more cellular markers of ER stress.
  5. 9
    The method of any one of claims 1-8, wherein the rAAV vector comprises nucleic acid encodes miR-708 and rhodopsin.
  6. 10
    The method of any one of claims 1-8, further comprising administering to the eye of the mammal a second rAAV viral particle comprising a second rAAV vector comprising nucleic acid encoding rhodopsin.
  7. 11
    A method for treating retinitis pigmentosa in a mammal, comprising administering to the eye of the mammal or the cell a rAAV viral particle comprising a rAAV vector comprising nucleic acid encoding a miR-708 and rhodopsin.
  8. 12
    The method of any one of claims 1-11, wherein the nucleic acid encoding miR-708 is operably linked to a promoter.
  9. 15
    The method of any one of claims 9-11, wherein the nucleic acid encoding rhodopsin is operably linked to a promoter.
  10. 22
    The method of any one of claims 12-21, wherein a sequence derived from a minute virus of mouse (MVM) intron is located 3’ to the promoter , wherein optionally the MMV intron comprises the nucleotide sequence of SEQ ID NO:23.
  11. 23
    The method of any one of claims 12-22, wherein the promoter further comprises i) a CMV enhancer; ii) a sequence derived from a photoreceptor specific transcription factor; iii) a sequence derived from a rod photoreceptor specific transcription factor; iv) a sequence derived from a neural retinal basic zipper factor; v) a sequence derived from a cone rod homeobox-containing transcription factor sequence; vi) a CMV enhancer and at least one or more of a sequence derived from a photoreceptor specific transcription factor, a sequence derived from a rod photoreceptor specific transcription factor, a sequence derived from a neural retinal basic zipper factor; a sequence derived from a cone rod homeobox-containing transcription factor sequence,; vii) a neural retinal basic leucine zipper factor, a CMV enhancer and an Opsin promoter (-500 to +17); viii) a neural retinal basic leucine zipper factor, a CMV enhancer, an Opsin promoter (-500 to +17), and an MVM intron; ix) a CMV enhancer comprising SEQ ID NO:29;x) a neural retinal basic leucine zipper factor sequence comprising SEQ ID NO:30;xi) a sequence derived from a cone rod homeobox-containing transcription factor sequence comprising SEQ ID NO:28;;xii) a CMV enhancer comprising SEQ ID NO:29 and at least one or more of a sequence derived from a photoreceptor specific transcription factor, a sequence derived from a rod photoreceptor specific transcription factor, a sequence derived from a neural retinal basic zipper factor comprising SEQ ID NO:30;a sequence derived from a cone rod homeobox-containing transcription factor sequence comprising SEQ ID NO:28;xiii) a neural retinal basic leucine zipper factor comprising SEQ ID NO:30, a CMV enhancer comprising SEQ ID NO:29 and an Opsin promoter (-500 to +17) comprising SEQ ID NO:22;or xiv) a neural retinal basic leucine zipper factor comprising SEQ ID NO:30, a CMV enhancer comprising SEQ ID NO:29, an Opsin promoter (-500 to +17) comprising SEQ ID NO:22, and an MVM intron comprising SEQ ID NO:23.
  12. 24
    The method of any one of claims 1-23, wherein the nucleic acid encoding miR-708 is embedded in an intron.
  13. 25
    The method of any one of claims 1-24, wherein the nucleic acid encoding miR-708 comprises an endogenous miR-708 scaffold or a miR-155 scaffold.
  14. 26
    The method of any one of claims 9-25 wherein the rhodopsin is human rhodopsin.
  15. 27
    The method of any one of claims 9-26, wherein the nucleic acid encoding rhodopsin comprises a substitution, insertion or deletion of nucleic acid in the miR-708 target sequence.
  16. 29
    The method of any one of claims 9-28, wherein the rhodopsin lacks the 3’ untranslatedregion (UTR) miR-708 target sequence.
  17. 30
    The method of any one of claims 9-29, wherein the nucleic acid encoding rhodopsin comprises a substitution, insertion or deletion of nucleic acid in the miR-708 target sequence wherein the miR-708 target sequence is SEQ ID NO:19.
  18. 31
    The method of any one of claims 9-30, wherein expression of the rhodopsin is refractory to suppression by miR-708.
  19. 32
    The method of any one of claims 1-31, wherein the nucleic acid encoding miR-708 comprises the nucleic acid of SEQ ID NO:1.
  20. 33
    The method of any one of claims 1-31, wherein the nucleic acid encoding miR-708 comprises a nucleic acid having about at least 85% identity to SEQ ID NO:1.
  21. 34
    The method of any one of claims 9-33, wherein the rhodopsin comprises the amino acid sequence of SEQ ID NO:2.
  22. 35
    The method of any one of claims 9-33, wherein the rhodopsin comprises an amino acid sequence having about at least 85% identity to SEQ ID NO:2.
  23. 36
    The method of any one of claims 9-34, wherein the nucleic acid encoding the rhodopsin comprises nucleic acid of SEQ ID NO:3.
  24. 37
    The method of any one of claims 9-34, wherein the nucleic acid encoding the rhodopsin comprises a nucleic acid having about 85% identity to SEQ ID NO:3.
  25. 38
    The method of any one of claims 1-8 or 10, wherein the AAV viral particle comprises a recombinant viral genome comprising a polynucleotide of SEQ ID NO:5.
  26. 39
    The method of any one of claims 1-9 or 11, wherein the AAV viral particle comprises a recombinant viral genome comprising a polynucleotide of SEQ ID NO:6 SEQ ID NO:7, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27.
  27. 40
    The method of any one of claims 1-8 or 10, wherein the AAV viral particle comprises a recombinant viral genome comprising a polynucleotide having about at least 85% identity to SEQ ID NO:5.
  28. 41
    The method of any one of claims 1-9 or 11, wherein the AAV viral particle comprises a recombinant viral genome comprising a polynucleotide having about at least 85% identity to SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27.
  29. 42
    The method of any one of claims 1-41, wherein the AAV viral particle and/or the second AAV viral particle comprises an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV2R471A, AAV2/2-7m8, AAV DJ, AAV2 N587A, AAV2 E548A, AAV2 N708A, AAV V708K, a goat AAV, AAV1/AAV2 chimeric, bovine AAV, or mouse AAV capsid rAAV2/HB0Vl serotype capsid.
  30. 43
    The method of any one of claims 1-42, wherein the rAAV viral particle and/or the second rAAV viral particle comprise an AAV serotype 5 capsid.
  31. 45
    The method of any one of claims 1-44, wherein the rAAV vector and/or the second rAAV vector comprise AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV2R471A, AAV DJ, a goat AAV, bovine AAV, or mouse AAV serotype inverted terminal repeats (ITRs).
  32. 46
    The method claim 45, wherein the rAAV vector and/or the second rAAV vector comprise AAV serotype 2 ITRs.
  33. 47
    The method of any one of claims 1-46, wherein the ITR and the capsid of the rAAV viral particle are derived from the same AAV serotype.
  34. 48
    The method of any one of claims 1-46, wherein the ITR and the capsid of the rAAV viral particles are derived from different AAV serotypes.
  35. 51
    The method of any one of claims 1-50, wherein the rAAV particles are injected into the subretinal space of the retina of the mammal.
  36. 53
    The method of any one of claims 1-51, wherein the rAAV particles are injected intravitreally to the mammal.
  37. 54
    The method of any one of claims 1-53, wherein at least 10-30% of the photoreceptor cells are transduced by the AAV.
  38. 55
    The method of any one of claims 1-54, wherein the mammal has a mutation in the endogenous rhodopsin gene.
  39. 57
    The method of any one of claims 1 or 3-56, wherein the retinitis pigmentosa is autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa.
  40. 58
    The method of any one of claims 1-59, wherein the mammal is a human.
  41. 62
    The method of any one of claims 1-60, wherein the rAAV viral particles are in a pharmaceutical composition, wherein optionally the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  42. 63
    A rAAV particle, and optionally a second rAAV particle according to any one of claims 1-62.
  43. 65
    A rAAV particle comprising nucleic acid encoding a miR-708.
  44. 68
    The rAAV particle of any one of claims 65-67, wherein the nucleic acid encoding miR-708 is operably linked to a promoter.
  45. 71
    The rAAV particle of any one of claims 66 or 67, wherein the nucleic acid encoding rhodopsin is operably linked to a promoter.
  46. 78
    The rAAV particle of any one of claims 68-77, wherein a sequence derived from a minute virus of mouse (MVM) intron is located 3’ to the promoter, wherein optionally the MMV intron comprises the nucleotide sequence of SEQ ID NO:23.
  47. 79
    The method of any one of claims 68-78, wherein the promoter further comprises i) a CMV enhancer; ii) a sequence derived from a photoreceptor specific transcription factor; iii) a sequence derived from a rod photoreceptor specific transcription factor; iv) a sequence derived from a neural retinal basic zipper factor; v) a sequence derived from a cone rod homeobox-containing transcription factor sequence; vi) a CMV enhancer and at least one or more of a sequence derived from a photoreceptor specific transcription factor, a sequence derived from a rod photoreceptor specific transcription factor, a sequence derived from a neural retinal basic zipper factor; a sequence derived from a cone rod homeobox-containing transcription factor sequence; vii) a neural retinal basic leucine zipper factor, a CMV enhancer and an Opsin promoter (-500 to +17); viii) a neural retinal basic leucine zipper factor, a CMV enhancer, an Opsin promoter (-500 to +17), and an MVM intron; ix) a CMV enhancer comprising SEQ ID NO:29;x) a neural retinal basic leucine zipper factor sequence comprising SEQ ID NO:30;xi) a sequence derived from a cone rod homeobox-containing transcription factor sequence comprising SEQ ID NO:28;;xii) a CMV enhancer comprising SEQ ID NO:29 and at least one or more of a sequence derived from a photoreceptor specific transcription factor, a sequence derived from a rod photoreceptor specific transcription factor, a sequence derived from a neural retinal basic zipper factor comprising SEQ ID NO:30;a sequence derived from a cone rod homeobox-containing transcription factor sequence comprising SEQ ID NO:28;xiii) a neural retinal basic leucine zipper factor comprising SEQ ID NO:30, a CMV enhancer comprising SEQ ID NO:29 and an Opsin promoter (-500 to +17) comprising SEQ ID NO:22;or xiv) a neural retinal basic leucine zipper factor comprising SEQ ID NO:30, a CMV enhancer comprising SEQ ID NO:29, an Opsin promoter (-500 to +17) comprising SEQ ID NO:22, and an MVM intron comprising SEQ ID NO:23.
  48. 80
    The rAAV particle of any one of claims 65-79, wherein the nucleic acid encoding miR-708 is embedded in an intron.
  49. 81
    The rAAV particle of any one of claims 65-80, wherein the nucleic acid encoding miR-708 comprises an endogenous miR-708 scaffold or a miR-155 scaffold.
  50. 82
    The rAAV particle of any one of claims 66-81, wherein the rhodopsin is human rhodopsin.
  51. 83
    The method of any one of claims 66-82, wherein the nucleic acid encoding rhodopsin comprises a substitution, insertion or deletion of nucleic acid in the miR-708 target sequence.
  52. 85
    The rAAV particle of any one of claims 66-84, wherein the rhodopsin lacks the 3’ UTR miR-708 target sequence.
  53. 86
    The rAAV particle of any one of claims 66-85, wherein the nucleic acid encoding rhodopsin comprises a substitution, insertion or deletion of nucleic acid in the miR-708 target sequence wherein the miR-708 target sequence is SEQ ID NO:19.
  54. 87
    The rAAV particle of any one of claims 65-86, wherein expression of the rhodopsin is refractory to suppression by miR-708.
  55. 88
    The rAAV particle of any one of claims 65-87, wherein the nucleic acid encoding miR-708 comprises the nucleic acid of SEQ ID NO:1.
  56. 89
    The rAAV particle of any one of claims 65-88, wherein the nucleic acid encoding miR-708 comprises a nucleic acid having about at least 85% identity to SEQ ID NO:1.
  57. 90
    The rAAV particle of any one of claims 66-89, wherein the rhodopsin comprises the amino acid sequence of SEQ ID NO:2.
  58. 91
    The rAAV particle of any one of claims 66-90, wherein the rhodopsin comprises an amino acid sequence having about at least 85% identity to SEQ ID NO:2.
  59. 92
    The rAAV particle of any one of claims 66-90, wherein the nucleic acid encoding the rhodopsin comprises nucleic acid of SEQ ID NO:3.
  60. 93
    The rAAV particle of any one of claims 66-90, wherein the nucleic acid encoding the rhodopsin comprises a nucleic acid having about 85% identity to SEQ ID NO:3.
  61. 95
    The rAAV particle of any one of claims 66 or 68-73, wherein the AAV viral particle comprises a recombinant viral genome comprising a polynucleotide of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27.
  62. 97
    The rAAV particle of any one of claims 66 or 68-73, wherein the AAV viral particle comprises a recombinant viral genome comprises a polynucleotide having about at least 85% identity to SEQ ID NO:6 SEQ ID NO:7, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27.
  63. 98
    The rAAV particle of any one of claims 65-97, wherein the AAV viral particle comprises an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV2R471A, AAV2/2-7m8, AAV DJ, AAV2 N587A, AAV2 E548A, AAV2 N708A, AAV V708K, a goat AAV, AAV1/AAV2 chimeric, bovine AAV, or mouse AAV capsid rAAV2/HB0Vl serotype capsid.
  64. 99
    The rAAV particle of any one of claims 65-98, wherein the rAAV viral particle comprises an AAV serotype 5 capsid.
  65. 101
    The rAAV particle of any one of claims 65-100, wherein the rAAV vector comprises AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV2R471A, AAV DJ, a goat AAV, bovine AAV, or mouse AAV serotype inverted terminal repeats (ITRs).
  66. 102
    The rAAV particle of any one of claims 65-101, wherein the vector comprises AAV serotype 2 ITRs.
  67. 103
    The rAAV particle of any one of claims 65-102, wherein the ITR and the capsid of the rAAV viral particle are derived from the same AAV serotype.
  68. 104
    The rAAV particle of any one of claims 65-102, wherein the ITR and the capsid of the rAAV viral particles are derived from different AAV serotypes.
  69. 107
    A composition comprising the rAAV particle of any one of claims 65-106.
  70. 108
    A composition comprising a rAAV particle comprising a rAAV vector comprising nucleic acid encoding miR-708 according to any one of claims 1-62, and optionally a second rAAV particle comprising a rAAV vector comprising nucleic acid encoding rhodopsin, used in the methods of any one of claims 1-62.
  71. 110
    The composition of any one of claims 107-108, wherein the composition is a pharmaceutical composition, wherein optionally the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  72. 111
    A kit comprising an effective amount of rAAV particles according to the methods of any one of claims 1-62.
  73. 112
    A kit comprising an effective amount of rAAV particles according to any one of claims 63-106.
  74. 113
    A kit comprising an effective amount of the composition of any one of claims 107110.
  75. 114
    A kit comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708.
  76. 115
    A kit comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708 and rhodopsin.
  77. 116
    A kit comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708 and an effective amount of second rAAV particles comprising a second rAAV vector comprising nucleic acid encoding rhodopsin.
  78. 117
    The kit of any one of claims 118-122, further comprising instructions for use of the rAAV particles in the treatment of retinitis pigmentosa and/or treatment of ER stress.
  79. 118
    An article of manufacture comprising an effective amount of rAAV particles according to the methods of any one of claims 1-62.
  80. 119
    An article of manufacture comprising an effective amount of rAAV particles according to any one of claims 63-106.
  81. 120
    An article of manufacture comprising an effective amount of the composition of any one of claims 107-110.
  82. 121
    An article of manufacture comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708.
  83. 122
    An article of manufacture comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708 rhodopsin.
  84. 123
    An article of manufacture comprising an effective amount of rAAV particles comprising a rAAV vector comprising nucleic acid encoding miR-708 and an effective amount of second rAAV particles comprising a second rAAV vector comprising nucleic acid encoding rhodopsin.
  85. 124
    A nucleic acid comprising an intron derived from an MVM.
  86. 128
    An expression construct comprising the nucleic acid of any one of claims 124-127.
Independent claims86