Antisense oligomers for treatment of conditions and diseases

• US 10,683,503 B2
• Filed: 09/05/2019
• Issued: 06/16/2020
• Est. Priority Date: 08/25/2017
• Status: Active Grant

• Current Assignee: Stoke Therapeutics, Inc.
• Original Assignee: Stoke Therapeutics, Inc.
• Inventors: Aznarez, Isabel, Han, Zhou
• Primary Examiner(s): Whiteman, Brian
• Application Number:
  US16/561,960
• Publication Number:
  US 20200024606A1
• Time in Patent Office: 285 Days
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/12 for grand-mal
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2320/33 Alteration of splicing
• CPC Class Codes: C12N 2320/35 based on a specific dosage / administration regimen
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

Alternative splicing events in SCN1A gene can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression, and therapeutic agents which can target the alternative splicing events in SCN1A gene can modulate the expression level of functional proteins in Dravet Syndrome patients and/or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition caused by SCN1A, SCN8A or SCN5A protein deficiency.

Claims

1. A pharmaceutical composition comprising an antisense oligomer that comprises a sequence selected from the group consisting of SEQ ID NOs:

21-61, 64-67, 210-250, 253-256 and 304-379, and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

21-61 and 64-67.

3. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

210-250 and 253-256.

4. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

304-379.

5. The pharmaceutical composition of claim 1, wherein the antisense oligomer is a sequence selected from the group consisting of SEQ ID NOs:

21-61, 64-67, 210-250, 253-256, and 304-379.

6. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a 2′

-O-methoxyethyl moiety.

7. The pharmaceutical composition of claim 6, wherein each nucleotide of the antisense oligomer comprises a 2′

-O-methoxyethyl moiety.

8. The pharmaceutical composition of claim 1, wherein the antisense oligomer consists of from 8 to 50 nucleobases.

9. The pharmaceutical composition of claim 1, wherein the antisense oligomer consists of from 12 to 20 nucleobases.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for intrathecal injection or intracerebroventricular injection.

11. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a backbone modification, a modified sugar moiety or a combination thereof.

16. The pharmaceutical composition of claim 1, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

32-35, 39, 40, 42-45, 49-51, 54-59, 66, 221-224, 228, 229, 231-234, 238-240, 243-248, 255, 304-308, 312-316, 318-324, 326-335, 337-346, 350-354, 356-362, 364-373 and 375-379.

17. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

32 or 221.

18. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

33 or 222.

19. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

42 or 231.

20. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

43 or 232.

21. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

44 or 233.

22. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

51 or 240.

23. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

54 or 243.

24. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

55 or 244.

25. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

56 or 245.

26. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

57 or 246.

27. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

58 or 247.

28. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

59 or 248.

29. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

304 or 342.

30. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

305 or 343.

31. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

306 or 344.

32. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

307 or 345.

33. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

308 or 346.

34. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

312 or 350.

35. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

313 or 351.

36. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

314 or 352.

37. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

315 or 353.

38. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

316 or 354.

39. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

318 or 356.

40. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

319 or 357.

41. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

320 or 358.

42. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

321 or 359.

43. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

322 or 360.

44. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

323 or 361.

45. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

324 or 362.

46. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

326 or 364.

47. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

327 or 365.

48. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

328 or 366.

49. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

329 or 367.

50. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

330 or 368.

51. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

331 or 369.

52. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

332 or 370.

53. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

333 or 371.

54. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

334 or 372.

55. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

335 or 373.

56. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

337 or 375.

57. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

338 or 376.

58. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

339 or 377.

59. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

340 or 378.

60. The pharmaceutical composition of claim 1, wherein the antisense oligomer is SEQ ID NO:

341 or 379.

61. The pharmaceutical composition of any one of claims 16-60, wherein the antisense oligomer comprises a 2′

-O-methoxyethyl moiety.

62. The pharmaceutical composition of any one of claims 16-60, wherein each nucleotide of the antisense oligomer comprises a 2′

-O-methoxyethyl moiety.

12. A composition comprising a viral vector encoding an antisense oligomer;

wherein the antisense oligomer binds to a targeted portion of a pre-mRNA that contains a non-sense mediated RNA decay-inducing exon (NMD exon mRNA) and that encodes Nav1.1 protein, whereby the antisense oligomer promotes exclusion of the NMD exon from the NMD exon mRNA encoding Nav1.1.

13. The composition of claim 12, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

21-67, 210-256 and 304-379.

14. The composition of claim 12, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

21-61, 64-67, 210-250, 253-256, and 304-379.

15. The composition of claim 12, wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:

32-35, 39, 40, 42-45, 49-51, 54-59, 66, 221-224, 228, 229, 231-234, 238-240, 243-248, 255, 304-308, 312-316, 318-324, 326-335, 337-346, 350-354, 356-362, 364-373 and 375-379.