GJB2 CONTROL ELEMENTS AND APPLICATION OPTIONS

RU2024123834A3Pending Publication Date: 2026-07-03DECIBEL THERAPEUTICS INC +1

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Patent Information

Authority / Receiving Office: RU · RU
Patent Type: Applications
Current Assignee / Owner: DECIBEL THERAPEUTICS INC
Filing Date: 2023-02-03
Publication Date: 2026-07-03

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Claims

1. A polynucleotide comprising a GJB2 promoter comprising a first region having at least 85% sequence identity with SEQ ID NO: 1 or a functional part or derivative thereof comprising at least one of SEQ ID NOs: 3-12, operably linked to a second region having at least 85% sequence identity with SEQ ID NO: 2 or a functional part or derivative thereof comprising at least one of SEQ ID NOs: 20-24, wherein the distance between the first region and the second region in the polynucleotide is no more than 1 kilobase (kb).

2. The polynucleotide of claim 1, wherein the first region has at least 85% sequence identity with SEQ ID NO:

1.

3. The polynucleotide of claim 2, wherein the first region has the sequence SEQ ID NO: 1 4. The polynucleotide of claim 1, wherein the first region has at least 85% sequence identity with any one of SEQ ID NOs: 3-19.

5. The polynucleotide of claim 4, wherein the first region has a sequence of any one of SEQ ID NOs: 3-19.

6. The polynucleotide of claim 5, wherein the first region has the sequence SEQ ID NO:

3.

7. The polynucleotide of any one of claims 1-6, wherein the second region has at least 85% sequence identity to SEQ ID NO:

2.

8. The polynucleotide of claim 7, wherein the second region has the sequence SEQ ID NO:

2.

9. The polynucleotide of any one of claims 1-6, wherein the second region has at least 85% sequence identity with any one of SEQ ID NOs: 20-28.

10. The polynucleotide of claim 9, wherein the second region has a sequence of any one of SEQ ID NOs: 20-28.

11. The polynucleotide of claim 10, wherein the second region has the sequence SEQ ID NO:

20.

12. The polynucleotide of claim 10, wherein the second region has the sequence SEQ ID NO:

21.

13. The polynucleotide of claim 10, wherein the second region has the sequence SEQ ID NO:

22.

14. The polynucleotide of claim 10, wherein the second region has the sequence SEQ ID NO:

25.

15. The polynucleotide of claim 10, wherein the second region has the sequence SEQ ID NO:

26.

16. The polynucleotide of any one of claims 1-15, wherein the first region is fused directly to the second region without a linker.

17. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

30.

18. The polynucleotide of claim 17, wherein the GJB2 promoter has the sequence of SEQ ID NO:

30.

19. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

31.

20. The polynucleotide of claim 19, wherein the GJB2 promoter has the sequence of SEQ ID NO:

31.

21. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

32.

22. The polynucleotide of claim 21, wherein the GJB2 promoter has the sequence of SEQ ID NO:

32.

23. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

33.

24. The polynucleotide of claim 23, wherein the GJB2 promoter has the sequence of SEQ ID NO:

33.

25. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

34.

26. The polynucleotide of claim 25, wherein the GJB2 promoter has the sequence of SEQ ID NO:

34.

27. The polynucleotide of claim 16, wherein the GJB2 promoter has at least 85% sequence identity to SEQ ID NO:

35.

28. The polynucleotide of claim 27, wherein the GJB2 promoter has the sequence of SEQ ID NO:

35.

29. A polynucleotide comprising a GJB2 promoter having at least 85% sequence identity to SEQ ID NO:

13.

30. A polynucleotide comprising a GJB2 promoter having at least 85% sequence identity to SEQ ID NO:

37.

31. The polynucleotide of any one of claims 1-30, wherein the GJB2 promoter is operably linked to a polynucleotide encoding an expression product.

32. The polynucleotide of claim 31, wherein the expression product is a protein, a short hairpin RNA (shRNA), an antisense oligonucleotide (ASO), a component of a gene editing system, or a microRNA.

33. The polynucleotide of claim 31, wherein the expression product is an expression product that is endogenously expressed in a GJB2-expressing cell.

34. The polynucleotide of claim 31, wherein the expression product is an expression product that is endogenously expressed in a GJB2-expressing inner ear cell.

35. The polynucleotide of claim 33 or 34, wherein the expression product is Gjb2 or Gjb6.

36. The polynucleotide of claim 31, wherein the expression product is a heterologous expression product.

37. The polynucleotide of any one of claims 1-36, wherein the polynucleotide further comprises a GJB2 enhancer operably linked to a GJB2 promoter.

38. The polynucleotide of claim 37, wherein the GJB2 enhancer has at least 85% sequence identity to the nucleotide sequence of any one of SEQ ID NOs: 52-63.

39. The polynucleotide of claim 37 or 38, wherein the GJB2 enhancer has the sequence of any one of SEQ ID NOs: 52-63.

40. The polynucleotide of any one of claims 37-39, wherein the GJB2 enhancer is located in the 5' direction from the promoter.

41. The polynucleotide of any one of claims 37-39, wherein the GJB2 enhancer is located in the 3' direction from the promoter.

42. A nucleic acid vector comprising a polynucleotide according to any one of claims 1-41.

43. The nucleic acid vector of claim 42, wherein the nucleic acid vector is a viral vector.

44. The nucleic acid vector of claim 43, wherein the viral vector is an adeno-associated viral vector.

45. A composition comprising a nucleic acid vector according to any one of claims 42-44 and a pharmaceutically acceptable carrier, diluent or excipient.

46. A method for expressing an expression product in a GJB2-expressing cell, comprising contacting the GJB2-expressing cell with a nucleic acid vector according to any one of claims 42-44 or a composition according to claim 45.

47. The method of claim 46, wherein the GJB2-expressing cell is a GJB2-expressing inner ear cell.

48. The method according to claim 46 or 47, wherein the contacting is carried out on the subject.

49. A method of treating a subject having or at risk of developing GJB2-associated hearing loss, comprising administering to the inner ear of the subject a therapeutically effective amount of a nucleic acid vector according to any one of claims 42-44 or a composition according to claim 45, wherein the expression product is Gjb2 or Gjb6.

50. The method of claim 49, wherein the GJB2-associated hearing loss is DFNB1 or DFNA3.

51. The method of claim 50, wherein the subject has a mutation in GJB2, a mutation in GJB6, or a mutation in both GJB2 and GJB6.

52. A method for inducing or enhancing cochlear hair cell regeneration in a subject in need thereof, comprising administering to the inner ear of the subject a therapeutically effective amount of a nucleic acid vector according to any one of claims 42-44 or a composition according to claim 45, wherein the nucleic acid vector comprises a GJB2 enhancer having at least 85% sequence identity with SEQ ID NO: 59, and the expression product is an expression product that can stimulate or enhance the proliferation or differentiation of cochlear supporting cells into cochlear hair cells.

53. A method of treating a subject having or at risk of developing hearing loss associated with damage or loss of cochlear hair cells, comprising administering to the inner ear of the subject a therapeutically effective amount of a nucleic acid vector according to any one of claims 42-44 or a composition according to claim 45, wherein the nucleic acid vector comprises a GJB2 enhancer having at least 85% sequence identity to SEQ ID NO: 59, and the expression product is an expression product that can stimulate or enhance the proliferation of cochlear supporting cells or the differentiation of cochlear supporting cells into cochlear hair cells.

54. The method according to claim 52 or 53, wherein the polynucleotide encoding the expression product is a polynucleotide specified in Table 5.

55. A method of treating a subject having or at risk of developing genetic hearing loss associated with a mutation in a gene that is endogenously expressed in the supporting cells of the cochlea, comprising administering to the inner ear of the subject a therapeutically effective amount of a nucleic acid vector according to any one of claims 42-44 or a composition according to claim 45, wherein the enhancer has at least 85% sequence identity to SEQ ID NO: 59, and the polynucleotide encoding the expression product is a wild-type form of the gene that is mutated in the supporting cells of the cochlea.

56. The method of claim 55, wherein the genetic hearing loss is associated with a disease specified in Table 6, and the polynucleotide encoding the expression product is a wild-type form of the gene that is mutated in said disease.