IP Library › Granted Patent US 12,697,399
Granted Patent B2
US 12,697,399 · App. 17/778,651 · Granted Aug 4, 2026

Microdystrophin gene therapy constructs and uses thereof

Inventors: Chunping Qiao (Rockville, MD); Devin McDougald (Boston, MA); Ye Liu (Clarksville, MD); Olivier Danos (Princeton, NJ)
Assignee: REGENXBIO INC.
A61K48/0058A61P21/00C07K14/4708C12N15/86C12N2750/14143C12N2750/14151C12N2750/14171
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Quick Facts
Patent No.
US 12,697,399
App. No.
17/778,651
Granted
Aug 4, 2026
Kind
B2
Abstract

Provided are gene constructs that encode a microdystrophin protein for use in gene therapy. The microdystrophin gene constructs and expression cassettes were engineered for improved therapy with respect to efficacy, potency and safety to the subject when expressed by a viral vector in muscle cells and/or CNS cells.

Claims (71)

1 . A recombinant adeno-associated virus (rAAV) particle comprising a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 79, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein.

2 . A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle, wherein the rAAV particle comprises a) a nucleic acid comprising a nucleotide sequence encoding the microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 79, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein, wherein the nucleic acid encoding the microdystrophin protein is delivered to the cell.

3 . The rAAV particle of claim 1 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 81, or a nucleotide sequence at least 85% identical to the nucleotide sequence of SEQ ID NO: 81, or the reverse complement thereof.

4 . The rAAV particle of claim 3 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 81.

5 . The rAAV particle of claim 1 , wherein the nucleic acid comprises a transcription regulatory element that promotes expression in muscle, wherein the transcription regulatory element is operably linked to the nucleotide sequence encoding the microdystrophin protein.

6 . The rAAV particle of claim 5 , wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof.

7 . The rAAV particle of claim 5 , wherein the nucleic acid comprises from 5′ to 3′:

a first adeno-associated virus (AAV) inverted terminal repeat (ITR) sequence-a transcription regulatory element sequence-the nucleotide sequence encoding the microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence.

8 . The rAAV particle of claim 7 , wherein the capsid protein comprises a) an amino acid sequence that is at least 95% identical to SEQ ID NO: 77, b) the amino acid sequence of SEQ ID NO: 77, c) an amino acid sequence that is at least 95% identical to SEQ ID NO: 78, or d) the amino acid sequence of SEQ ID NO: 78.

9 . An rAAV particle comprising a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 1, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein.

10 . The rAAV particle of claim 9 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 20 or a nucleotide sequence at least 85% identical to the nucleotide sequence of SEQ ID NO: 20 or the reverse complement thereof.

11 . The rAAV particle of claim 10 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 20.

12 . The rAAV particle of claim 9 wherein the nucleic acid comprises a transcription regulatory element that promotes expression in muscle, wherein the transcription regulatory element is operably linked to the nucleotide sequence encoding the microdystrophin protein.

13 . The rAAV particle of claim 12 , wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof.

14 . The rAAV particle of claim 12 , wherein the nucleic acid comprises from 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-the nucleotide sequence encoding the microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence.

15 . The rAAV particle of claim 14 , wherein the capsid protein comprises a) an amino acid sequence that is at least 95% identical to SEQ ID NO: 77, b) the amino acid sequence of SEQ ID NO: 77, c) an amino acid sequence that is at least 95% identical to SEQ ID NO: 78, or d) the amino acid sequence of SEQ ID NO: 78.

16 . The rAAV particle of claim 15 , wherein the capsid protein comprises the amino acid sequence of SEQ ID NO: 77.

17 . An rAAV particle comprising a) a nucleic acid comprising 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-a nucleotide sequence encoding a microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence,

wherein the microdystrophin protein comprises the amino acid sequence of SEQ ID NO: 1, wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof, and

b) a capsid comprising a capsid protein comprising the amino acid sequence of SEQ ID NO: 77.

18 . A pharmaceutical composition comprising i) a rAAV particle comprising a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 79, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein, and ii) a pharmaceutically acceptable carrier.

19 . A pharmaceutical composition comprising i) a rAAV particle comprising a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 1, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein, and ii) a pharmaceutically acceptable carrier.

20 . A pharmaceutical composition comprising i) a rAAV particle comprising a) a nucleic acid comprising 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-a nucleotide sequence encoding a microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence,

wherein the microdystrophin protein comprises the amino acid sequence of SEQ ID NO: 1,

wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof, and b) a capsid comprising a capsid protein comprising the amino acid sequence of SEQ ID NO: 77, and ii) a pharmaceutically acceptable carrier.

21 . The rAAV particle of claim 7 , wherein each of the AAV ITR sequences is an AAV2 ITR sequence.

22 . The rAAV particle of claim 8 , wherein the capsid protein comprises the amino acid sequence of SEQ ID NO: 77.

23 . The rAAV particle of claim 14 , wherein each of the AAV ITR sequences is an AAV2 ITR sequence.

24 . The rAAV particle of claim 17 , wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 53 or a nucleotide sequence that is 95% identical to SEQ ID NO: 53.

25 . The rAAV particle of claim 24 , wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 53.

26 . A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle, wherein the rAAV particle comprises a) the nucleic acid comprising a nucleotide sequence encoding the microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 1, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein, wherein the nucleic acid encoding the microdystrophin protein is delivered to the cell.

27 . A method of treating a dystrophinopathy in a human subject in need thereof, the method comprising:

administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a rAAV particle, wherein the rAAV particle comprises a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 79, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein,

wherein the administration results in expression of the microdystrophin protein in a muscle cell of the subject thereby treating the dystrophinopathy in the subject.

28 . The method of claim 27 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 81 or a nucleotide sequence at least 85% identical to the nucleotide sequence of SEQ ID NO: 81, or the reverse complement thereof.

29 . The method of claim 28 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 81.

30 . The method of claim 27 , wherein the nucleic acid comprises a transcription regulatory element that promotes expression in muscle, wherein the transcription regulatory element is operably linked to the nucleotide sequence encoding the microdystrophin protein.

31 . The method of claim 30 , wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof.

32 . The method of claim 30 , wherein the nucleic acid comprises a nucleotide sequence comprising from 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-the nucleotide sequence encoding the microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence.

33 . The method of claim 32 , wherein each of the AAV ITR sequences is an AAV2 ITR sequence.

34 . The method of claim 27 , wherein the capsid protein comprises a) an amino acid sequence that is at least 95% identical to SEQ ID NO: 77, b) the amino acid sequence of SEQ ID NO: 77, c) an amino acid sequence that is at least 95% identical to SEQ ID NO: 78, or d) the amino acid sequence of SEQ ID NO: 78.

35 . The method of claim 34 , wherein the capsid protein comprises the amino acid sequence of SEQ ID NO: 77.

36 . The method of claim 27 , wherein the dystrophinopathy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, or the subject is a female carrier of DMD or BMD.

37 . The method of claim 36 , wherein the dystrophinopathy is DMD.

38 . A method of treating a dystrophinopathy in a human subject in need thereof, the method comprising:

administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) particle, wherein the rAAV particle comprises a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO: 1, or the reverse complement of the nucleotide sequence, and b) a capsid comprising a capsid protein,

wherein the administration results in expression of a microdystrophin protein in a muscle cell of the subject thereby treating the dystrophinopathy in the subject.

39 . The method of claim 38 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 20 or a nucleotide sequence at least 85% identical to the nucleotide sequence of SEQ ID NO: 20, or the reverse complement thereof.

40 . The method of claim 39 , wherein the nucleotide sequence encoding the microdystrophin protein comprises the nucleotide sequence of SEQ ID NO: 20.

41 . The method of claim 38 , wherein the nucleic acid comprises a transcription regulatory element that promotes expression in muscle, wherein the transcription regulatory element is operably linked to the nucleotide sequence encoding the microdystrophin protein.

42 . The method of claim 41 , wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof.

43 . The method of claim 41 , wherein the nucleic acid comprises a nucleotide sequence comprising from 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-the nucleotide sequence encoding the microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence.

44 . The method of claim 43 , wherein each of the AAV ITR sequences is an AAV2 ITR sequence.

45 . The method of claim 38 , wherein the capsid protein comprises a) an amino acid sequence that is at least 95% identical to SEQ ID NO: 77, b) the amino acid sequence of SEQ ID NO: 77, c) an amino acid sequence that is at least 95% identical to SEQ ID NO: 78, or d) the amino acid sequence of SEQ ID NO: 78.

46 . The method of claim 45 , wherein the capsid protein comprises the amino acid sequence of SEQ ID NO: 77.

47 . The method of claim 38 , wherein the dystrophinopathy is DMD, BMD, X-linked dilated cardiomyopathy, or the subject is a female carrier of DMD or BMD.

48 . The method of claim 47 , wherein the dystrophinopathy is DMD.

49 . A method of treating Duchenne muscular dystrophy (DMD) in a human subject in need thereof, the method comprising:

administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) particle, wherein the rAAV particle comprises

a) a nucleic acid comprising from 5′ to 3′:

a first AAV ITR sequence-a transcription regulatory element sequence-a nucleotide sequence encoding a microdystrophin protein-a polyadenylation sequence-a second AAV ITR sequence,

wherein the microdystrophin protein comprises the amino acid sequence of SEQ ID NO: 1,

wherein the transcription regulatory element is an SPc5-12 promoter or a transcriptionally active portion thereof, and

b) a capsid comprising a capsid protein comprising the amino acid sequence of SEQ ID NO: 77, wherein the administration results in expression of the microdystrophin protein in a muscle cell of the subject thereby treating the DMD in the subject.

50 . The method of claim 49 , wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 53 or a nucleotide sequence that is 95% identical to SEQ ID NO: 53.

51 . The method of claim 50 , wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 53.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 9, 2022
From: QIAO, CHUNPING; MCDOUGALD, DEVIN; LIU, YE; DANOS, OLIVIER
To: REGENXBIO INC.
Reel/Frame 060751/0048 →
Continuity (3)
Provisional Application 63024933 · May 14, 2020
Provisional Application 62941719 · Nov 28, 2019
Related Publication 20230270886A1 · Aug 31, 2023
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