IP Library › Granted Patent US 11,053,494
Granted Patent B2
US 11,053,494 · App. 15/502,702 · Granted Jul 6, 2021

Methods and materials for activating an internal ribosome entry site in exon 5 of the DMD gene

Inventors: Kevin Flanigan (Columbus, OH); Nicolas Wein (Columbus, OH); Stephen Wilton (Perth, AU)
Assignees: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL; THE UNIVERSITY OF WESTERN AUSTRALIA
C12N15/113A61K9/0019A61K31/573A61K31/58A61K31/712C12N2310/11C12N2310/315C12N2310/3231C12N2310/3233C12N2310/346C12N2310/3513C12N2310/3519C12N2320/31C12N2320/33C12N2330/51C12N2750/14143C12N2840/203
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Quick Facts
Patent No.
US 11,053,494
App. No.
15/502,702
Granted
Jul 6, 2021
Kind
B2
Abstract

The present invention relates to the delivery of oligomers for treating patients with a 5′ mutation in their DMD gene other than a DMD exon 2 duplication. The invention provides methods and materials for activating an internal ribosome entry site in exon 5 of the DMD gene resulting in translation of a functional truncated isoform of dystrophin. The methods and materials can be used for the treatment of muscular dystrophies arising from 5′ mutations in the DMD gene such as Duchenne Muscular Dystrophy or Becker Muscular Dystrophy.

Claims (29)

1. A method of ameliorating Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in a patient with a 5′ mutation in a DMD gene but without a DMD exon 2 duplication, the method comprising the step of administering to the patient a recombinant adeno-associated virus (rAAV) comprising a DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprising

(a) the nucleotide sequence set forth in SEQ ID NO: 6 or

(b) a nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 10.

2. The method of claim 1 wherein the progression of a dystrophic pathology is inhibited in the patient.

3. The method of claim 1 wherein muscle function is improved in the patient.

4. The method of claim 3 wherein the improvement in muscle function is an improvement in muscle strength.

5. The method of claim 3 wherein the improvement in muscle function is an improvement in stability in standing and walking.

6. The method of claim 1 wherein the genome of the rAAV lacks adeno-associated virus rep and cap DNA.

7. The method of claim 1 wherein the genome of the rAAV is a self-complementary genome and/or single-stranded genome.

8. The method of claim 1 , wherein the rAAV is r-AAV1, r-AAV2, r-AAV3, r-AAV4, r-AAV5, r-AAV6, r-AAV7, r-AAV8, r-AAV9, r-AAV10, r-AAV11, or r-AAVrh74.

9. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence set forth in SEQ ID NO: 5.

10. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises the nucleotide sequence set forth in SEQ ID NO: 6.

11. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence set forth in SEQ ID NO: 7.

12. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence set forth in SEQ ID NO: 8.

13. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 9.

14. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises the nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 10.

15. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 11.

16. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises the nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 12.

17. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises two or more copies of the nucleotide sequence set forth in SEQ ID NO: 6.

18. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises two or more copies of the nucleotide sequence set forth in SEQ ID NO: 7.

19. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises at least two copies of the polynucleotide comprising the sequence set forth in SEQ ID NO: 6 and at least two copies of the polynucleotide comprising the sequence set forth in SEQ ID NO: 7.

20. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises two copies of the polynucleotide comprising the sequence set forth in SEQ ID NO: 6 and two copies of the polynucleotide comprising the sequence set forth in SEQ ID NO: 7.

21. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises two or more copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 10.

22. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct further comprises two or more copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 11.

23. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises at least two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 10 and at least two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 11.

24. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 10 and two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 11.

25. The method of claim 1 , wherein the DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprises two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 10 and two copies of the nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 11.

26. The method of claim 8 wherein the rAAV is r-AAV1, r-AAV6, r-AAV8, r-AAV9, or r-AAV rh74.

27. The method of claim 1 , 6 , 7 , or 26 , further comprising administering a glucocorticoid to the patient.

Assignments (4)
CONFIRMATORY LICENSE Recorded Sep 26, 2022
From: CHILDREN'S HOSPITAL COLUMBUS
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 061536/0728 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR NAME PREVIOUSLY RECORDED AT REEL: 042300 FRAME: 0883. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT . Recorded Feb 9, 2021
From: WILTON, STEPHEN
To: UNIVERSITY OF WESTERN AUSTRALIA
Reel/Frame 055262/0981 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2017
From: FLANIGAN, KEVIN; WEIN, NICOLAS
To: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL
Reel/Frame 042083/0335 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2017
From: WILTON, STEVEN
To: UNIVERSITY OF WESTERN AUSTRALIA
Reel/Frame 042300/0883 →
Continuity (2)
Provisional Application 62035395 · Aug 9, 2014
Related Publication 20170218366A1 · Aug 3, 2017