Capsid polypeptides and methods of their use.

Claims

CLAIMS 1. Capsid polypeptide, characterized in that it comprises a valine at a position corresponding to I601 of capsid polypeptide VP1 of SEQ ID NO:1, and optionally one, two or three or all four of: (a) an alanine, arginine, serine, threonine, valine at a position corresponding to T593 of capsid polypeptide VP1 of SEQ ID NO:1; (b) an alanine, tryptophan or tyrosine at a position corresponding to W595 of capsid polypeptide VP1 of SEQ ID NO:1; (c) a leucine at a position corresponding to V596 of capsid polypeptide VP1 of SEQ ID NO:1; and (d) a serine or threonine at a position corresponding to N598 of capsid polypeptide VP1 of SEQ ID NO:

1.

2. Capsid polypeptide, characterized in that it comprises: (a) alanine or serine at a position corresponding to T593 of capsid polypeptide VP1 of SEQ ID NO:1; (b) a leucine at a position corresponding to V596 of capsid polypeptide VP1 of SEQ ID NO:1; and (c) a serine or threonine at a position corresponding to N598 of capsid polypeptide VP1 of SEQ ID NO:

1.

3. Capsid polypeptide according to claim 2, characterized in that it comprises a serine at a position corresponding to N598 of the capsid polypeptide VP1 of SEQ ID NO:

1.

4. Capsid polypeptide according to claim 2, characterized in that it comprises a threonine at a position corresponding to N598 of the capsid polypeptide VP1 of SEQ ID NO:

1. Petition 870250078616, dated 03 / 09 / 2025, page 993 / 1025 2 / 8 5. Capsid polypeptide, characterized in that it comprises: (a) an alanine, tryptophan or tyrosine at a position corresponding to W595 of capsid polypeptide VP1 of SEQ ID NO:1; (b) a leucine at a position corresponding to V596 of capsid polypeptide VP1 of SEQ ID NO:1; and (c) a threonine at a position corresponding to N598 of capsid polypeptide VP1 of SEQ ID NO:

1.

6. Capsid polypeptide according to claim 5, characterized in that it comprises an alanine at a position corresponding to W595 of the capsid polypeptide VP1 of SEQ ID NO:

1.

7. Capsid polypeptide, characterized in that it comprises: (a) an alanine or serine at a position corresponding to T593 of the capsid polypeptide VP1 of SEQ ID NO:1; (b) an alanine, tryptophan or tyrosine at a position corresponding to W595 of the capsid polypeptide VP1 of SEQ ID NO:1; (c) a leucine at a position corresponding to V596 of the capsid polypeptide VP1 of SEQ ID NO:1; and (d) a serine or threonine at a position corresponding to N598 of the capsid polypeptide VP1 of SEQ ID NO:

1.

8. Capsid polypeptide, characterized in that it comprises: (a) an alanine, arginine, serine, threonine, valine at a position corresponding to T593 of capsid polypeptide VP1 of SEQ ID NO:1; (b) an alanine, tryptophan or tyrosine at a position corresponding to W595 of capsid polypeptide VP1 of SEQ ID NO:1; (c) a leucine at a position corresponding to V596 of capsid polypeptide VP1 of SEQ ID NO:1; and (d) a threonine at a position corresponding to N598 of capsid polypeptide VP1 of SEQ ID NO:

1.

9. Capsid polypeptide according to any one of claims 1 to 8, characterized in that it comprises a glutamic acid at a position corresponding to D551 of the capsid polypeptide VP1 of SEQ ID NO:

1.

10. Capsid polypeptide according to any one of claims 1 to 9, characterized in that it comprises a threonine at a position corresponding to Q579 of the capsid polypeptide VP1 of SEQ ID NO:

1.

11. Capsid polypeptide according to any one of claims 1 to 9, characterized in that it comprises a valine at a position corresponding to Q579 of the capsid polypeptide VP1 of SEQ ID NO:

1.

12. Capsid polypeptide according to any one of claims 1 to 11, characterized in that it comprises an alanine at a position corresponding to Q592 of the capsid polypeptide VP1 of SEQ ID NO:

1.

13. Capsid polypeptide according to any one of claims 1 to 11, characterized in that it comprises an asparagine at a position corresponding to Q592 of the capsid polypeptide VP1 of SEQ ID NO:

1.

14. Capsid polypeptide according to any one of claims 1 to 11, characterized in that it comprises a glutamine at a position corresponding to Q592 of the capsid polypeptide VP1 of SEQ ID NO:

1.

15. Capsid polypeptide, characterized in that it comprises 6, 7 or all 8 mutations of the VAR-2 mutation set compared with the VP1 capsid polypeptide of SEQ ID Petition 870250078616, dated 03 / 09 / 2025, page 995 / 1025 4 / 8 NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared with the VP1 capsid polypeptide of SEQ ID NO:

1.

16. Capsid polypeptide, characterized in that it comprises 5, 6, or all 7 mutations of the VAR-3 mutation set compared to the VP1 capsid polypeptide of SEQ ID NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared to the VP1 capsid polypeptide of SEQ ID NO:

1.

17. Capsid polypeptide, characterized in that it comprises 4, 5, or all 6 mutations of the VAR-11 mutation set compared with the VP1 capsid polypeptide of SEQ ID NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared with the VP1 capsid polypeptide of SEQ ID NO:

1.

18. Capsid polypeptide, characterized in that it comprises 4, 5, or all 6 mutations of the VAR-40 mutation set compared with the VP1 capsid polypeptide of SEQ ID NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared with the VP1 capsid polypeptide of SEQ ID NO:

1.

19. Capsid polypeptide, characterized in that it comprises 4, 5 or all 6 mutations of the VAR-42 mutation set compared with the VP1 capsid polypeptide of SEQ ID NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared with the VP1 capsid polypeptide of SEQ ID NO:

1.

20. Capsid polypeptide, characterized in that it comprises 6, 7, or all 8 mutations of the VAR-54 mutation set compared with the VP1 capsid polypeptide of SEQ ID NO:1, as shown in Table 24, preferably wherein the mutations comprise the V596 and N598 mutations and optionally a mutation in Q579 and / or T593 compared with the VP1 capsid polypeptide of SEQ ID NO:

1.

21. Capsid polypeptide according to any one of claims 1 to 20, characterized in that the sequence has an edit distance of (a) 12 or less or (b) 10 or less to a capsid polypeptide VP1 of SEQ ID NO:1 or the VP2 or VP3 portion thereof.

22. Capsid polypeptide according to any one of claims 1 to 20, characterized in that it comprises an amino acid sequence having at least 95% sequence identity with a VP1 capsid polypeptide of SEQ ID NO:1 or the VP2 or VP3 portion thereof.

23. Capsid polypeptide according to any one of claims 1 to 22, characterized in that it is a VP1 capsid polypeptide.

24. Capsid polypeptide according to any one of claims 1 to 22, characterized in that it is a VP2 capsid polypeptide.

25. Capsid polypeptide according to any one of claims 1 to 22, characterized in that it is a VP3 capsid polypeptide.

26. Nucleic acid, characterized in that it comprises a nucleotide sequence encoding a capsid polypeptide as defined in any of claims 1 to 25.

27. Virus particle, characterized in that it comprises a capsid polypeptide as defined in any one of claims 1 to 25.

28. Virus particle according to claim 27, characterized in that it comprises a nucleic acid comprising a payload (for example, a heterologous transgene) and one or more regulatory elements.

29. Virus particle according to claim 28, characterized in that one or more regulatory elements comprise a promoter.

30. Virus particle according to claim 29, characterized in that the promoter is a constitutive promoter.

31. Virus particle according to claim 29, characterized in that the promoter is a CNS-specific promoter.

32. Virus particle according to claim 29, characterized in that the promoter is a muscle-specific promoter.

33. Modified host cell, characterized in that it comprises a nucleic acid encoding a capsid polypeptide as defined in any one of claims 1 to 25.

34. Host cell according to claim 33, characterized in that it is a packaging cell lineage.

35. Host cell according to claim 33 or 34, characterized in that it comprises a nucleic acid encoding a rep protein.

36. Host cell according to any one of claims 33 to 35, characterized in that it comprises a nucleic acid comprising one or more auxiliary sequences.

37. Host cell according to any one of claims 33 to 36, characterized in that it is configured to package a virus particle as defined in any one of claims 27 to 32.

38. A method for producing a virus particle comprising a capsid polypeptide, characterized in that it comprises introducing a nucleic acid molecule as defined in claim 26 into a cell and collecting said virus particles from the same.

39. A method for producing a virus particle comprising a capsid polypeptide, characterized in that it comprises culturing a cell modified to express a capsid polypeptide as defined in any one of claims 1 to 25 and collecting virus particles therefrom.

40. Method according to claim 38 or 39, characterized in that the cell is a host cell as defined in any one of claims 33 to 37.

41. Method of administering a payload (e.g., a nucleic acid) to a cell, characterized in that it comprises (a) contact of the cell with a virus particle comprising the capsid peptide as defined in any one of claims 1 to 25 and a payload; or (b) contact of the cell with the virus particle as defined in any one of claims 27 to 32.

42. Method according to claim 42, characterized in that the cell is a CNS cell.

43. Method of administering a payload (for example, a nucleic acid) to an individual, characterized in that it comprises: (a) administering to the individual a virus particle comprising the capsid polypeptide as defined in any one of claims 1 to 25 and the payload; or (b) administering to the individual the virus particle as defined in any one of claims 27 to 32.

44. Method according to claim 43, characterized in that the virus particle delivers the payload to the CNS.

45. A method for treating a disease or condition in an individual, characterized in that it comprises administering to the individual in an amount effective for treating the disease or condition: (a) a virus particle comprising the capsid polypeptide as defined in any one of claims 1 to 25 and a heterologous nucleic acid sequence encoding a therapeutic product suitable for treating the disease or condition; (b) a virus particle comprising a capsid polypeptide encoded by the nucleic acid molecule as defined in claim 26 and a heterologous nucleic acid sequence encoding a therapeutic product suitable for treating the disease or condition; or (c) the virus particle as defined in any one of claims 27 to 32; or (d) a composition, for example, a pharmaceutical composition, comprising the virus particle of (a) and, optionally, a pharmaceutically acceptable carrier.

46. ​​Method according to claim 45, characterized in that the disease or condition is a disease or condition of the CNS.

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