IP Library › Granted Patent US 12,281,321
Granted Patent B2
US 12,281,321 · App. 17/279,878 · Granted Apr 22, 2025

Frataxin expression constructs having engineered promoters and methods of use thereof

Inventors: Holger Patzke (Lexington, MA); Jinzhao Hou (Lexington, MA); Hongxing Wang (Lexington, MA); Yanqun Shu (Lexington, MA); Martin Goulet (Lexington, MA); Dinah Wen-Yee Sah (Lexington, MA)
Assignee: Voyager Therapeutics, Inc.
C12N15/86A61K47/02A61K47/10A61K48/005C07K14/47C12N2830/008
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Quick Facts
Patent No.
US 12,281,321
App. No.
17/279,878
Granted
Apr 22, 2025
Kind
B2
Abstract

The disclosure relates to compositions and methods for altering, e.g., enhancing, the expression of frataxin (FXN), whether in vitro and/or in vivo including, but not limited to, the exploitation of engineered promoters. Such compositions include delivery via administration of an adeno-associated viral (AAV) particle. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, or suspected of having Friedreich's ataxia or another neuromuscular or neurological condition resulting from a deficiency in the quantity and/or function of frataxin or associated with decreased expression or protein levels of frataxin.

Claims (42)

1. An adeno-associated viral (AAV) vector genome comprising an engineered promoter and a nucleic acid sequence encoding a frataxin protein, wherein the engineered promoter consists of a sequence that has at least 90% sequence identity to SEQ ID NO: 1742 over the full length of the engineered promoter.

2. The AAV vector genome of claim 1 , wherein the engineered promoter consists of a sequence that has at least 95% sequence identity to SEQ ID NO: 1742 over the full length of the engineered promoter.

3. The AAV vector genome of claim 1 , wherein the engineered promoter consists of a sequence that has at least 99% sequence identity to SEQ ID NO: 1742 over the full length of the engineered promoter.

4. The AAV vector genome of claim 1 , wherein the engineered promoter consists of SEQ ID NO: 1742.

5. The AAV vector genome of claim 1 , wherein the frataxin protein comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1725, 1726, or 1727.

6. The AAV vector genome of claim 1 , wherein the frataxin protein comprises an amino acid sequence of SEQ ID NO: 1725, 1726, or 1727.

7. The AAV vector genome of claim 1 , wherein the frataxin protein comprises an amino acid sequence of SEQ ID NO: 1725.

8. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein has at least 80% sequence identity to a fragment of SEQ ID NO: 1728, 1729, or 1730.

9. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein comprises a fragment of SEQ ID NO: 1728, 1729, or 1730.

10. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein comprises nucleotides 221-853 of SEQ ID NO: 1728.

11. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein has at least 80% sequence identity to SEQ ID NO: 1823 or 1824.

12. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein is SEQ ID NO: 1823 or 1824.

13. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein comprises SEQ ID NO: 1823 or 1824.

14. The AAV vector genome of claim 1 , wherein the AAV vector genome further comprises a 5′ inverted terminal repeat (ITR).

15. The AAV vector genome of claim 14 , wherein the 5′ ITR is an AAV2 ITR.

16. The AAV vector genome of claim 1 , wherein the AAV vector genome further comprises a 3′ ITR.

17. The AAV vector genome of claim 16 , wherein the 3′ ITR is an AAV2 ITR.

18. The AAV vector genome of claim 1 , wherein the AAV vector genome further comprises a 5′ inverted terminal repeat (ITR), an intron, a microRNA (miR) binding site, a polyadenylation (polyA) sequence, a filler sequence, a 3′ ITR.

19. The AAV vector genome of claim 18 , wherein the intron comprises an enhancer sequence.

20. The AAV vector of claim 18 , wherein: the 5′ ITR has at least 95% sequence identity to SEQ ID NO: 1811, the intron has at least 90% sequence identity to SEQ ID NO: 1816, the nucleic acid sequence encoding the frataxin protein has at least 90% identity to SEQ ID NO: 1824, the miR binding site has at least 90% identity to SEQ ID NO: 1826 or 1827, the polyA sequence has at least 90% sequence identity to SEQ ID NO: 1828, the filler sequence has at least 90% sequence identity to SEQ ID NO: 1841, and/or the 3′ ITR has at least 95% sequence identity to SEQ ID NO: 1812.

21. The AAV vector of claim 20 , wherein: the 5′ ITR comprises SEQ ID NO: 1811, the intron comprises SEQ ID NO: 1816, the nucleic acid sequence encoding the frataxin protein comprises SEQ ID NO: 1824, the miR binding site comprises SEQ ID NO: 1826 or 1827, the polyA sequence comprises SEQ ID NO: 1828, the filler sequence comprises SEQ ID NO: 1841, and/or the 3′ ITR comprises SEQ ID NO: 1812.

22. The AAV vector genome of claim 18 , wherein the AAV vector genome further comprises three copies of a microRNA (miR) binding site.

23. The AAV vector genome of claim 22 , wherein the three copies of a miR binding site comprises SEQ ID NO: 1826.

24. The AAV vector genome of claim 1 , wherein the AAV vector genome further comprises at least one microRNA (miR) binding site.

25. The AAV vector genome of claim 24 , wherein the at least one miR binding site comprises a sequence that has at least 90% sequence identity to SEQ ID NO: 1827.

26. The AAV vector genome of claim 24 , wherein the at least one miR binding site comprises SEQ ID NO: 1827.

27. An AAV particle comprising the AAV vector genome of claim 1 .

28. A pharmaceutical composition comprising the AAV particle of claim 27 and a pharmaceutically acceptable excipient.

29. A method of treating Friedreich's Ataxia or another disorder associated with decreased frataxin protein levels in a subject in need thereof, comprising administering to the subject an effective amount of the AAV particle of claim 27 .

30. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein has at least 90% sequence identity to SEQ ID NO: 1823 or 1824.

31. The AAV vector genome of claim 1 , wherein the nucleic acid sequence encoding the frataxin protein has at least 95% sequence identity to SEQ ID NO: 1823 or 1824.

32. An adeno-associated viral (AAV) vector genome comprising a sequence that has at least 90% sequence identity to SEQ ID NO: 1797.

33. The AAV vector genome of claim 32 , wherein the AAV vector genome comprises a sequence that has at least 95% sequence identity to SEQ ID NO: 1797.

34. An AAV particle comprising the AAV vector genome of claim 32 .

35. A cell comprising the AAV vector genome of claim 32 .

36. A pharmaceutical composition comprising the AAV particle of claim 34 and a pharmaceutically acceptable excipient.

37. A method of treating Friedreich's Ataxia or another disorder associated with decreased frataxin protein levels in a subject in need thereof, comprising administering to the subject an effective amount of the AAV particle of claim 34 .

38. An adeno-associated virus (AAV) vector genome comprising the sequence of SEQ ID NO: 1797.

39. An AAV particle comprising the AAV vector genome of claim 38 .

40. A cell comprising the AAV vector genome of claim 38 .

41. A pharmaceutical composition comprising the AAV particle of claim 39 and a pharmaceutically acceptable excipient.

42. A method of treating Friedreich's Ataxia or another disorder associated with decreased frataxin protein levels in a subject in need thereof, comprising administering to the subject an effective amount of the AAV particle of claim 39 .

Assignments (2)
CHANGE OF ADDRESS Recorded Jul 16, 2025
From: VOYAGER THERAPEUTICS, INC.
To: VOYAGER THERAPEUTICS, INC.
Reel/Frame 071992/0540 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 30, 2021
From: PATZKE, HOLGER; HOU, JINZHAO; WANG, HONGXING; SHU, YANQUN; GOULET, MARTIN; SAH, DINAH WEN-YEE
To: VOYAGER THERAPEUTICS, INC.
Reel/Frame 055767/0530 →
Continuity (3)
Provisional Application 62901769 · Sep 17, 2019
Provisional Application 62738519 · Sep 28, 2018
Related Publication 20210395776A1 · Dec 23, 2021
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