EXON SKIPPING OLIGOMER CONJUGATES FOR MUSCULAR DYSTROPHY

• US 20180177814A1
• Filed: 12/13/2017
• Published: 06/28/2018
• Est. Priority Date: 12/19/2016
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: PASSINI, Marco A., HANSON, Gunnar J.
• Granted Patent: US 10,888,578 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/111 spanning the whole gene, or a large part of it

Abstract

Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 51 skipping are described.

Claims

1. An antisense oligomer conjugate of Formula (I):

2. The antisense oligomer conjugate of claim 1, wherein each Nu is independently cytosine (C), guanine (G), thymine (T), adenine (A), 5-methylcytosine (5mC), uracil (U), or hypoxanthine (I).

3. The antisense oligomer conjugate of claim 1, wherein the targeting sequence is SEQ ID NO:

1 (5′

-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′

), wherein each thymine (T) is optionally uracil (U).

4. The antisense oligomer conjugate of claim 1, wherein:

Tail is

5. The antisense oligomer conjugate of claim 1, wherein:

Tail is

12. A pharmaceutical composition, comprising the antisense oligomer conjugate of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof, wherein the subject has a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1.

14. The method of claim 13, wherein the antisense oligomer conjugate is administered weekly.

15. The method of claim 13, wherein the antisense oligomer conjugate is administered biweekly.

16. The method of claim 13, wherein the antisense oligomer conjugate is administered every third week.

17. The method of claim 13, wherein the antisense oligomer conjugate is administered monthly.

18. A method of restoring an mRNA reading frame to induce dystrophin production in a subject having a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1.

19. The method of claim 18, wherein the antisense oligomer conjugate is administered weekly.

20. The method of claim 18, wherein the antisense oligomer conjugate is administered biweekly.

21. The method of claim 18, wherein the antisense oligomer conjugate is administered every third week.

22. The method of claim 18, wherein the antisense oligomer conjugate is administered monthly.

23. A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof, wherein the subject has a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12.

24. A method of restoring an mRNA reading frame to induce dystrophin production in a subject having a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12.

25. A method of excluding exon 51 from dystrophin pre-mRNA during mRNA processing in a subject having a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12.

26. A method of binding exon 51 of a dystrophin pre-mRNA in a subject having a mutation of the dystrophin gene that is amenable to exon 51 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12.

27. The method of claim 13, wherein the subject is human.

28. The method of claim 18, wherein the subject is human.

29. The method of claim 23, wherein the subject is human.

30. The method of claim 26, wherein the subject is human.

6. An antisense oligomer conjugate of Formula (II):

7. The antisense oligomer conjugate of claim 6, wherein each X is

8. The antisense oligomer conjugate of claim 6, wherein the antisense oligomer is of Formula (IIA):

9. The antisense oligomer conjugate of claim 8, wherein each X is

10. An antisense oligomer conjugate of Formula (IV):

11. The antisense oligomer conjugate of claim 10, wherein the antisense oligomer is of Formula (IVA):