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1. WO2020160163 - COMPOSÉS ET MÉTHODES PERMETTANT DE RÉDUIRE L'EXPRESSION DE L'APP

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CLAIMS:

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked

nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of an APP RNA, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked

nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 12, 13, 14, 15, 16, 17, or 18 nucleobases of any of SEQ ID NOS: 12-501; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

3. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked

nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases of any of SEQ ID NOS: 502-516; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

4. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked

nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleobases of any of SEQ ID NOS: 517-665, 814-840 or 867-888; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

5. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked

nucleosides wherein the nucleobase sequence of the modified oligonucleotide is complementary to at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases of:

an equal length portion of nucleobases 40-78 of SEQ ID NO: 1;

an equal length portion of nucleobases 69-146 of SEQ ID NO: 1;

an equal length portion of nucleobases 83-129 of SEQ ID NO: 1;

an equal length portion of nucleobases 83-246 of SEQ ID NO: 1;

an equal length portion of nucleobases 94-225 of SEQ ID NO: 1;

an equal length portion of nucleobases 194-231 of SEQ ID NO: 1;

an equal length portion of nucleobases 194-238 of SEQ ID NO: 1;

an equal length portion of nucleobases 236-268 of SEQ ID NO: 1;

an equal length portion of nucleobases 258-288 of SEQ ID NO: 1;

an equal length portion of nucleobases 285-311 of SEQ ID NO: 1;

an equal length portion of nucleobases 296-321 of SEQ ID NO: 1; an equal length portion of nucleobases 307-330 of SEQ ID NO: 1; an equal length portion of nucleobases 329-352 of SEQ ID NO: 1; an equal length portion of nucleobases 330-352 of SEQ ID NO: 1; an equal length portion of nucleobases 339-383 of SEQ ID NO: 1; an equal length portion of nucleobases 415-439 of SEQ ID NO: 1; an equal length portion of nucleobases 413-477 of SEQ ID NO: 1; an equal length portion of nucleobases 415-477 of SEQ ID NO: 1; an equal length portion of nucleobases 477-506 of SEQ ID NO: 1; an equal length portion of nucleobases 477-523 of SEQ ID NO: 1; an equal length portion of nucleobases 477-541 of SEQ ID NO: 1; an equal length portion of nucleobases 530-557 of SEQ ID NO: 1; an equal length portion of nucleobases 581-638 of SEQ ID NO: 1; an equal length portion of nucleobases 636-661 of SEQ ID NO: 1; an equal length portion of nucleobases 652-697 of SEQ ID NO: 1; an equal length portion of nucleobases 728-821 of SEQ ID NO: 1; an equal length portion of nucleobases 770-821 of SEQ ID NO: 1; an equal length portion of nucleobases 920-950 of SEQ ID NO: 1; an equal length portion of nucleobases 1006-1049 of SEQ ID NO: 1; an equal length portion of nucleobases 1152-1179 of SEQ ID NO: 1; an equal length portion of nucleobases 1227-1265 of SEQ ID NO: 1; an equal length portion of nucleobases 1227-1274 of SEQ ID NO: 1; an equal length portion of nucleobases 1268-1332 of SEQ ID NO: 1; an equal length portion of nucleobases 1268-1311 of SEQ ID NO: 1; an equal length portion of nucleobases 1289-1332 of SEQ ID NO: 1; an equal length portion of nucleobases 1518-1543 of SEQ ID NO: 1; an equal length portion of nucleobases 1531-1593 of SEQ ID NO: 1; an equal length portion of nucleobases 1544-1593 of SEQ ID NO: 1; an equal length portion of nucleobases 1634-1657 of SEQ ID NO: 1; an equal length portion of nucleobases 1778-1800 of SEQ ID NO: 1; an equal length portion of nucleobases 1882-1908 of SEQ ID NO: 1; an equal length portion of nucleobases 2051-2074 of SEQ ID NO: 1; an equal length portion of nucleobases 2360-3117 of SEQ ID NO: 1; an equal length portion of nucleobases 2402-3117 of SEQ ID NO: 1; an equal length portion of nucleobases 2360-2655 of SEQ ID NO: 1; an equal length portion of nucleobases 2402-2655 of SEQ ID NO: 1; an equal length portion of nucleobases 2675-3054 of SEQ ID NO: 1; or

an equal length portion of nucleobases 3192-3277 of SEQ ID NO: 3;

wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

6. The oligomeric compound of any of claims 1-5, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, 85%, 90%, 95%, or 100% complementary to any of the nucleobase sequences of SEQ ID NO: 1-7 when measured across the entire nucleobase sequence of the modified oligonucleotide.

7. The oligomeric compound of any of claims 1-6, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

8. The oligomeric compound of claim 7, wherein at least one nucleoside of the modified

oligonucleotide comprises a modified sugar moiety.

9. The oligomeric compound of claim 8, wherein at least one modified nucleoside of the modified oligonucleotide comprises a bicyclic sugar moiety.

10. The oligomeric compound of claim 9, wherein at least one modified nucleoside of the modified oligonucleotide comprises a bicyclic sugar moiety having a 2’ -4’ bridge, wherein the 2’-4’ bridge is selected from -O-CH2-; and -0-CH(CH3)-.

11. The oligomeric compound of any of claims 5-10, wherein at least one modified nucleoside of the modified oligonucleotide comprises a non-bicyclic modified sugar moiety.

12. The oligomeric compound of claim 11, wherein at least one modified nucleoside of the modified oligonucleotide comprises a bicyclic sugar moiety having a 2’ -4’ bridge and at least one nucleoside comprising a non-bicyclic modified sugar moiety.

13. The oligomeric compound of claim 11 or 12, wherein the non-bicyclic modified sugar moiety is a 2’- MOE modified sugar moiety, a 2’-OMe modified sugar moiety, or a 2’-F modified sugar moiety.

14. The oligomeric compound of any of claims 1-13, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.

15. The oligomeric compound of claim 14, wherein at least one modified nucleoside of the modified oligonucleotide comprises a sugar surrogate selected from morpholino and PNA.

16. The oligomeric compound of any of claims 1-15, wherein the modified oligonucleotide comprises at least one modified intemucleoside linkage.

17. The oligomeric compound of claim 16, wherein each intemucleoside linkage of the modified

oligonucleotide is a modified intemucleoside linkage.

18. The oligomeric compound of claim 17 or 18, wherein at least one intemucleoside linkage is a

phosphorothioate intemucleoside linkage.

19. The oligomeric compound of claim 16 or 18, wherein the modified oligonucleotide comprises at least one phosphodiester intemucleoside linkage.

20. The oligomeric compound of any of claims 16, 18, or 19, wherein each intemucleoside linkage is independently selected from a phosphodiester intemucleoside linkage or a phosphorothioate intemucleoside linkage.

21. The oligomeric compound of any of claims 1-20, wherein the modified oligonucleotide comprises a modified nucleobase.

22. The oligomeric compound of claim 21, wherein the modified nucleobase is a 5-methyl cytosine.

23. The oligomeric compound of any of claims 1-22 wherein the modified oligonucleotide consists of 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 16-18, 18-22, 18-25, 18-20, 20-25, or 21-23 linked nucleosides.

24. The oligomeric compound of any of claims 1-23, wherein the modified oligonucleotide consists of 18 linked nucleosides.

25. The oligomeric compound of any of claims 1-23, wherein the modified oligonucleotide consists of 20 linked nucleosides.

26. The oligomeric compound of any of claims 1-23, wherein the modified oligonucleotide consists of 21 linked nucleosides.

27. The oligomeric compound of any of claims 1-23, wherein the modified oligonucleotide consists of 23 linked nucleosides.

28. The oligomeric compound of any of claims 1-27, wherein the oligomeric compound is an R ase H compound.

29. The oligomeric compound of claim 28, wherein the modified oligonucleotide is a gapmer.

30. The oligomeric compound of any of claims 1-29, wherein the modified oligonucleotide has a sugar motif comprising:

a 5’-region consisting of 1-6 linked 5’-region nucleosides;

a central region consisting of 6-10 linked central region nucleosides; and

a 3’-region consisting of 1-6 linked 3’-region nucleosides;

wherein the 3’-most nucleoside of the 5’-region and the 5’-most nucleoside of the 3’-region comprise modified sugar moieties, and

each of the central region nucleosides is selected from a nucleoside comprising a 2 -b-ϋ- deoxyribosyl sugar moiety and a nucleoside comprising a 2’-substituted sugar moiety, wherein the central region comprises at least six nucleosides comprising a 2’- -D-deoxyribosyl sugar moiety and no more than two nucleosides comprising a 2’-substituted sugar moiety.

31. The oligomeric compound of any of claims 1-26 or 28-29, wherein the modified oligonucleotide has a sugar motif comprising:

a 5’-region consisting of 1-6 linked 5’-region nucleosides;

a central region consisting of 6-10 linked central region nucleosides; and

a 3’-region consisting of 1-6 linked 3’-region nucleosides; wherein

each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2’- -D-deoxyribosyl sugar moiety.

32. The oligomeric compound of claim 31, wherein the modified oligonucleotide has a sugar motif comprising:

a 5’-region consisting of 5 linked 5’-region nucleosides;

a central region consisting of 10 linked central region nucleosides; and

a 3’-region consisting of 5 linked 3’-region nucleosides; wherein

each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises either a cEt modified sugar moiety or a 2’-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2’- -D-deoxyribosyl sugar moiety.

33. The oligomeric compound of any of claims 1-27, wherein the oligomeric compound is an RNAi compound.

34. The oligomeric compound of any of claims 1-33, wherein the oligomeric compound comprises an antisense RNAi oligonucleotide comprising a targeting region comprising at least 15 contiguous nucleobases, wherein the targeting region is at least 90% complementary to an equal-length portion of an APP R A.

35. The oligomeric compound of claim 34, wherein the targeting region of the antisense RNAi

oligonucleotide is at least 95% complementary or is 100% complementary to the equal length portion of an APP RNA.

36. The oligomeric compound of any of claims 34-35, wherein the targeting region of the antisense RNAi oligonucleotide comprises at least 19, 20, 21, or 25 contiguous nucleobases.

37. The oligomeric compound of any of claims 34-36, wherein the APP RNA has the nucleobase

sequence of any of SEQ ID NOs: 1-7.

38. The oligomeric compound of any of claims 34-37 wherein at least one nucleoside of the antisense RNAi oligonucleotide comprises a modified sugar moiety selected from: 2’-F, 2’-OMe, 2’-NMA, LNA, and cEt; or a sugar surrogate selected from GNA, and UNA.

39. The oligomeric compound of any of claims 34-35, wherein each nucleoside of the antisense RNAi oligonucleotide comprises a modified sugar moiety or a sugar surrogate.

40. The oligomeric compound of any of claims 34-39 wherein at least 80%, at least 90%, or 100% of the nucleosides of the antisense RNAi oligonucleotide comprises a modified sugar moiety selected from 2’-F and 2’-OMe.

41. The oligomeric compound of any of claims 34-40, comprising a stabilized phosphate group attached to the 5’ position of the 5’-most nucleoside of the antisense RNAi oligonucleotide.

42. The oligomeric compound of claim 41, wherein the stabilized phosphate group comprises a

cyclopropyl phosphonate or an (E)-\ inyl phosphonate.

43. The oligomeric compound of any of claims 1-42, wherein the oligomeric compound is a single- stranded oligomeric compound.

44. The oligomeric compound of any of claims 1-43, consisting of the modified oligonucleotide or the RNAi antisense oligonucleotide.

45. The oligomeric compound of any of claims 1-44, comprising a conjugate group comprising a

conjugate moiety and a conjugate linker.

46. The oligomeric compound of claim 45, wherein the conjugate linker consists of a single bond.

47. The oligomeric compound of claim 45, wherein the conjugate linker is cleavable.

48. The oligomeric compound of claim 45, wherein the conjugate linker comprises 1-3 linker- nucleosides.

49. The oligomeric compound of any of claims 45-48, wherein the conjugate group is attached to the 5’- end of the modified oligonucleotide or the antisense RNAi oligonucleotide.

50. The oligomeric compound of any of claims 45-48 wherein the conjugate group is attached to the 3’- end of the modified oligonucleotide or the antisense RNAi oligonucleotide.

51. The oligomeric compound of any of claims 1-50, comprising a terminal group.

52. The oligomeric compound of any of claims 1-47 or 49-51, wherein the oligomeric compound does not comprise linker-nucleosides.

53. An oligomeric duplex, comprising a first oligomeric compound comprising an antisense RNAi oligonucleotide of any of claims 34-52 and a second oligomeric compound comprising a sense RNAi oligonucleotide consisting of 17 to 30 linked nucleosides, wherein the nucleobase sequence of the sense RNAi oligonucleotide comprises an antisense-hybridizing region comprising least 15 contiguous nucleobases wherein the antisense-hybridizing region is at least 90% complementary to an equal length portion of the antisense RNAi oligonucleotide.

54. The oligomeric duplex of claim 53, wherein the sense RNAi oligonucleotide consists of 18-25, 20- 25, or 21-23 linked nucleosides.

55. The oligomeric duplex of claim 53, wherein the sense RNAi oligonucleotide consists of 21 or 23 linked nucleosides.

56. The oligomeric duplex of any of claims 53-55, wherein 1-4 3’-most nucleosides of the antisense or the sense RNAi oligonucleotide are overhanging nucleosides.

57. The oligomeric duplex of any of claims 53-56, wherein 1-4 5’-most nucleosides of the antisense or sense RNAi oligonucleotide are overhanging nucleosides.

58. The oligomeric duplex of any of claims 53-55, wherein the duplex is blunt ended at the 3’-end of the antisense RNAi oligonucleotide.

59. The oligomeric duplex of any of claims 53-55, wherein the duplex is blunt ended at the 5’-end of the antisense RNAi oligonucleotide.

60. The oligomeric duplex of any of claims 53-59, wherein at least one nucleoside of the sense RNAi oligonucleotide comprises a modified sugar moiety selected from: 2’-F, 2’-OMe, LNA, cEt, or a sugar surrogate selected from GNA, and UNA.

61. The oligomeric duplex of claim 60, wherein each nucleoside of the sense RNAi oligonucleotide comprises a modified sugar moiety or a sugar surrogate.

62. The oligomeric duplex of claim 61, wherein at least 80%, at least 90%, or 100% of the nucleosides of the sense RNAi oligonucleotide comprises a modified sugar moiety selected from 2’-F and 2’- OMe.

63. The oligomeric duplex of any of claims 53-62, wherein at least one nucleoside of the sense RNAi oligonucleotide comprises a modified nucleobase.

64. The oligomeric duplex of any of claims 53-63, wherein at least one intemucleoside linkage of the sense RNAi oligonucleotide is a modified intemucleoside linkage.

65. The oligomeric duplex of claim 64, wherein at least one intemucleoside linkage of the sense RNAi oligonucleotide is a phosphorothioate intemucleoside linkage.

66. The oligomeric duplex of any of claims 53-65, wherein the compound comprises 1-5 abasic sugar moieties attached to one or both ends of the antisense or sense RNA oligonucleotide.

67. The oligomeric duplex of any of claims 53-66, consisting of the antisense RNAi oligonucleotide and the sense RNAi oligonucleotide.

68. The oligomeric duplex of any of claims 53-66, wherein the second oligomeric compound comprises a conjugate group comprising a conjugate moiety and a conjugate linker.

69. The oligomeric duplex of claim 68, wherein the conjugate linker consists of a single bond.

70. The oligomeric duplex of claim 69, wherein the conjugate linker is cleavable.

71. The oligomeric duplex of claim 69, wherein the conjugate linker comprises 1-3 linker-nucleosides.

72. The oligomeric duplex of any of claims 69-71, wherein the conjugate group is attached to the 5’-end of the sense RNAi oligonucleotide.

73. The oligomeric duplex of any of claims 69-71 wherein the conjugate group is attached to the 3’-end of the sense RNAi oligonucleotide.

74. The oligomeric duplex of any of claims 69-71, wherein the conjugate group is attached via the 2’ position of a ribosyl sugar moiety at an internal position of the sense RNAi oligonucleotide.

75. The oligomeric compound of any of claims 45-50 or the oligomeric duplex of any of claims 68-74, wherein at least one conjugate group comprises a Ci6 alkyl group.

76. The oligomeric duplex of claim 53, wherein the second oligomeric compound comprises a terminal group.

77. A pharmaceutical composition comprising an oligomeric compound of any of claims 1-52 or an oligomeric duplex of claim 53-76 and a pharmaceutically acceptable carrier or diluent.

78. The pharmaceutical composition of claim 77, wherein the pharmaceutically acceptable diluent is artificial cerebral spinal fluid, sterile saline, or PBS.

79. The pharmaceutical composition of claim 78, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and sterile saline.

80. A method comprising administering to an animal a pharmaceutical composition of any of claims 77- 79.

81. A method of treating a disease associated with APP comprising administering to an individual having or at risk for developing a disease associated with APP a therapeutically effective amount of a pharmaceutical composition according to any of claims 77-79; and thereby treating the disease associated with APP.

82. The method of claim 81, wherein the APP -associated disease is Alzheimer’s Disease, Alzheimer’s Disease in a Down Syndrome patient, or Cerebral Amyloid Angiopathy.

83. The method of any of claims 80-82 wherein at least one symptom or hallmark of the APP-associated disease is ameliorated.

84. The method of claim 83, wherein the symptom or hallmark is cognitive impairment, including a decline in memory and language skills, behavioral and psychological symptoms such as apathy and lack of motivation, gait disturbances and seizures, progressive dementia, and/or abnormal amyloid deposits.