IP Library › Granted Patent US 10,385,320
Granted Patent B2
US 10,385,320 · App. 15/367,734 · Granted Aug 20, 2019

Recombinant adeno-associated virus capsids with enhanced human skeletal muscle tropism

Inventors: Mark A. Kay (Los Altos, CA); Nicole K. Paulk (Menlo Park, CA)
Assignee: The Board of Trustees of the Leland Stanford Junior University
C12N7/00A61K48/00A61K48/0058C07K14/005C12N9/22C12N15/86C12Y301/00C12N2710/10322C12N2710/10331C12N2710/10334C12N2710/10351C12N2750/14122C12N2750/14143C12N2750/14145C12N2750/14151
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Quick Facts
Patent No.
US 10,385,320
App. No.
15/367,734
Granted
Aug 20, 2019
Kind
B2
Abstract

The present invention relates to variant AAV capsid polypeptides, wherein the variant AAV capsid polypeptides exhibit increased transduction and/or tropism in human muscle tissue or cells as compared non-variant parent capsid polypeptides.

Claims (41)

1. A variant adeno-associated virus (AAV) capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits increased transduction or tropism in human skeletal muscle tissue or cells as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide comprises a sequence selected from the group consisting of AAV-NP6 (SEQ ID NO: 1), AAV-NP20 (SEQ ID NO: 2), AAV-NP22(SEQ ID NO: 3), AAV-NP36 (SEQ ID NO: 4), AAV-NP66 (SEQ ID NO: 5), AAV-NP81 (SEQ ID NO: 6), and AAV-NP94 (SEQ ID NO: 7).

2. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide exhibits increased transduction as compared to a non-variant parent capsid polypeptide.

3. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide exhibits increased tropism as compared to a non-variant parent capsid polypeptide.

4. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide further exhibits an enhanced neutralization profile as compared to a non-variant parent capsid polypeptide.

5. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide further exhibits increased transduction or tropism in one or more non-muscle human tissues as compared to a non-variant parent capsid polypeptide.

6. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide exhibits increased transduction of human muscle tissue or cells in vivo as compared to a non-variant parent capsid polypeptide.

7. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide exhibits increased transduction of human muscle tissue or cells in vitro as compared to a non-variant parent capsid polypeptide.

8. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide exhibits increased transduction of a human muscle tissue explant ex vivo as compared to a non-variant parent capsid polypeptide.

9. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide is part of a functional AAV capsid, wherein said functional AAV capsid packages a nucleic acid sequence selected from the group consisting of a non-coding RNA, a protein coding sequence, an expression cassette, a multi-expression cassette, a sequence for homologous recombination, a genomic gene targeting cassette, and a therapeutic expression cassette.

10. The variant AAV capsid polypeptide of claim 9 , wherein said nucleic acid sequence is contained within an AAV vector.

11. The variant AAV capsid polypeptide of claim 9 , wherein said expression cassette is a CRISPR/CAS expression system.

12. The variant AAV capsid polypeptide of claim 9 , wherein said therapeutic expression cassette encodes a therapeutic protein or antibody.

13. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP22 (SEQ ID NO: 3).

14. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP66 (SEQ ID NO: 5).

15. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP6 (SEQ ID NO: 1).

16. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP20 (SEQ ID NO: 2).

17. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP36 (SEQ ID NO: 4).

18. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP81 (SEQ ID NO: 6).

19. The variant AAV capsid polypeptide of claim 1 , wherein said variant AAV capsid polypeptide sequence is AAV-NP94 (SEQ ID NO: 7).

20. The variant AAV capsid polypeptide of claim 9 , wherein said variant AAV capsid polypeptide results in increased nucleic acid expression as compared to a non-variant parent capsid polypeptide.

21. A variant adeno-associated virus (AAV) capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits enhanced neutralization profile as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide comprises a sequence selected from the group consisting of AAV-NP6 (SEQ ID NO: 1), AAV-NP20 (SEQ ID NO: 2), AAV-NP22 (SEQ ID NO: 3), AAV-NP36 (SEQ ID NO: 4), AAV-NP66 (SEQ ID NO: 5), AAV-NP81 (SEQ ID NO: 6), and AAV-NP94 (SEQ ID NO: 7).

22. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide exhibits an enhanced neutralization profile against pooled human immunoglobulins as compared to a non-variant parent capsid polypeptide.

23. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide further exhibits increased transduction or tropism in human skeletal muscle tissue or cells as compared to a non-variant parent capsid polypeptide.

24. The variant AAV capsid polypeptide of claim 23 , wherein said variant AAV capsid polypeptide exhibits increased transduction as compared to a non-variant parent capsid polypeptide.

25. The variant AAV capsid polypeptide of claim 23 , wherein said variant AAV capsid polypeptide exhibits increased tropism as compared to a non-variant parent capsid polypeptide.

26. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide further exhibits increased transduction or tropism in one or more non-muscle human tissues as compared to a non-variant parent capsid polypeptide.

27. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide exhibits increased transduction of human muscle tissue or cells in vivo as compared to a non-variant parent capsid polypeptide.

28. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide exhibits increased transduction of human muscle tissue or cells in vitro as compared to a non-variant parent capsid polypeptide.

29. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide exhibits increased transduction of a human muscle tissue explant ex vivo as compared to a non-variant parent capsid polypeptide.

30. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide is part of a functional AAV capsid, wherein said functional AAV capsid packages a nucleic acid sequence selected from the group consisting of a non-coding RNA, a protein coding sequence, an expression cassette, a multi-expression cassette, a sequence for homologous recombination, a genomic gene targeting cassette, and a therapeutic expression cassette.

31. The variant AAV capsid polypeptide of claim 30 , wherein said nucleic acid sequence is contained within an AAV vector.

32. The variant AAV capsid polypeptide of claim 30 , wherein said expression cassette is a CRISPR/CAS expression system.

33. The variant AAV capsid polypeptide of claim 30 , wherein said therapeutic expression cassette encodes a therapeutic protein or antibody.

34. The variant AAV capsid polypeptide of claim 30 , wherein said variant AAV capsid polypeptide results in increased nucleic acid expression as compared to a non-variant parent capsid polypeptide.

35. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP22 (SEQ ID NO: 3).

36. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP66 (SEQ ID NO: 5).

37. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP6 (SEQ ID NO: 1).

38. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP20 (SEQ ID NO: 2).

39. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP36 (SEQ ID NO: 4).

40. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP81 (SEQ ID NO: 6).

41. The variant AAV capsid polypeptide of claim 21 , wherein said variant AAV capsid polypeptide sequence is AAV-NP94 (SEQ ID NO: 7).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 14, 2017
From: KAY, MARK A; PAULK, NICOLE K
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 041255/0990 →
Continuity (4)
Provisional Application 62336078 · May 13, 2016
Provisional Application 62268428 · Dec 16, 2015
Provisional Application 62262289 · Dec 2, 2015
Related Publication 20170159026A1 · Jun 8, 2017
Cited By (6)
US 12,258,332 US 12,472,268 US 12,544,437 US 12,611,436 US 12,649,006 US 12,686,874