IP Library › Granted Patent US 11,760,999
Granted Patent B2
US 11,760,999 · App. 17/174,452 · Granted Sep 19, 2023

RAAV-based compositions and methods for treating amyotrophic lateral sclerosis

Inventors: Christian Mueller (Worcester, MA); Robert H. Brown, Jr. (Worcester, MA)
Assignee: University of Massachusetts
C12N15/113C12N15/111C12N15/1137C12N15/86C12Y115/01001C12N2310/14C12N2310/141C12N2320/32C12N2330/51C12N2750/14143
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Quick Facts
Patent No.
US 11,760,999
App. No.
17/174,452
Granted
Sep 19, 2023
Kind
B2
Abstract

The invention relates to inhibitory nucleic acids and rAAV-based compositions, methods and kits useful for treating Amyotrophic Lateral Sclerosis.

Claims (29)

1. A method of inhibiting expression of C9orf72 in a subject in need thereof, the method comprising administering to the subject an effective amount of a synthetic microRNA (miRNA) that targets a C9orf72 RNA transcript, wherein the synthetic miRNA specifically binds to a nucleic acid sequence of the RNA transcript, wherein the nucleic acid sequence of the RNA transcript bound by the synthetic miRNA is encoded by a nucleic acid sequence as set forth in any one of SEQ ID NO: 1, 3, 4, 5, or 8.

2. The method of claim 1 , wherein the synthetic miRNA further comprises flanking regions of miR-155.

3. The method of claim 2 , wherein the RNA transcript is a pre-mRNA transcript.

4. The method of claim 2 , wherein the RNA transcript comprises a G 4 C 2 hexanucleotide repeat.

5. The method of claim 3 , wherein the pre-mRNA transcript is a C9orf72 V 1 isoform transcript.

6. The method of claim 3 , wherein the pre-mRNA transcript is a C9orf72 V 3 isoform transcript.

7. The method of claim 3 , wherein the pre-mRNA transcript is not a C9orf72 V 2 isoform transcript.

8. The method of claim 1 , wherein the RNA transcript comprises an intron.

9. A synthetic microRNA (miRNA) that targets a C9orf72 RNA transcript, wherein the synthetic miRNA specifically binds to a nucleic acid sequence of the RNA transcript, wherein the nucleic acid sequence of the RNA transcript bound by the synthetic miRNA is encoded by a nucleic acid sequence as set forth in any one of SEQ ID NO: 1, 3, 4, 5, or 8, and wherein the synthetic miRNA further comprises flanking regions of miR-155.

10. The synthetic miRNA of claim 9 , wherein the RNA transcript is a pre-mRNA transcript.

11. The synthetic miRNA of claim 9 , wherein the RNA transcript comprises a G 4 C 2 hexanucleotide repeat.

12. The synthetic miRNA of claim 10 , wherein the pre-mRNA transcript is a C9orf72 V 1 isoform transcript.

13. The synthetic miRNA of claim 10 , wherein the pre-mRNA transcript is a C9orf72 V 3 isoform transcript.

14. The synthetic miRNA of claim 10 , wherein the pre-mRNA transcript is not a C9orf72 V 2 isoform transcript.

15. The synthetic miRNA of claim 9 , wherein the RNA transcript comprises an intron.

16. A recombinant nucleic acid encoding a synthetic microRNA (miRNA) that targets a C 9 orf72 RNA transcript, wherein the synthetic miRNA specifically binds to a nucleic acid sequence of the RNA transcript, wherein the nucleic acid sequence of the RNA transcript bound by the synthetic miRNA is encoded by a nucleic acid sequence as set forth in any one of SEQ ID NO: 1, 3, 4, 5, or 8, and wherein the nucleic acid sequence encoding the synthetic miRNA is flanked by AAV inverted terminal repeats (ITRs).

17. The recombinant nucleic acid of claim 16 , further comprising a promoter operably linked with a region encoding the synthetic miRNA.

18. The recombinant nucleic acid of claim 17 , wherein the promoter is a tissue-specific promoter.

19. The recombinant nucleic acid of claim 17 , wherein the promoter is an RNA polymerase II promoter.

20. The recombinant nucleic acid of claim 19 , wherein the polymerase II promoter is a chicken β-actin (CBA) promoter.

21. The recombinant nucleic acid of claim 17 , wherein the promoter is an RNA polymerase III promoter.

22. The recombinant nucleic acid of claim 21 , wherein the polymerase III promoter is a U6 promoter.

23. A recombinant adeno-associated virus (rAAV) comprising a recombinant nucleic acid encoding a synthetic miRNA that targets a C9orf72 RNA transcript, wherein the synthetic miRNA specifically binds to a nucleic acid sequence of the RNA transcript, wherein the nucleic acid sequence of the RNA transcript bound by the synthetic miRNA is encoded by a nucleic acid sequence as set forth in any one of SEQ ID NO: 1, 3, 4, 5, or 8, and further comprising AAV inverted terminal repeats (ITRs).

24. The rAAV of claim 23 , further comprising one or more capsid proteins of one or more AAV serotypes selected from the group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV.Rh10, AAV11, and variants thereof.

25. The rAAV of claim 23 , wherein the synthetic miRNA comprises flanking regions of miR-155.

26. The rAAV of claim 23 , wherein the RNA transcript is a pre-mRNA transcript.

27. The rAAV of claim 23 , wherein the RNA transcript comprises a G 4 C 2 hexanucleotide repeat.

28. The rAAV of claim 23 , wherein the RNA transcript comprises an intron.

29. A composition comprising the rAAV of claim 23 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 12, 2021
From: MUELLER, CHRISTIAN; BROWN, ROBERT H., JR.
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 056211/0846 →
Continuity (4)
Continuation 16295621 · Mar 7, 2019
Continuation 15126688
Provisional Application 61955189 · Mar 18, 2014
Related Publication 20210246450A1 · Aug 12, 2021
Cited By (3)
US 12,312,587 US 12,529,051 US 12,662,669