EXON SKIPPING COMPOSITIONS FOR TREATING MUSCULAR DYSTROPHY

• US 20140329881A1
• Filed: 03/14/2014
• Published: 11/06/2014
• Est. Priority Date: 03/14/2013
• Status: Abandoned Application

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Bestwick, Richard K., Frank, Diane Elizabeth, Schnell, Fred Joseph
• Application Number:
  US14/214,480
• Publication Number:
  US 20140329881A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2310/3535 Nitrogen
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/33 Alteration of splicing
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon 44 skipping are described.

Claims

1. An antisense oligomer of 20-50 nucleotides in length capable of binding a selected target to induce exon skipping in the human dystrophin gene, wherein said antisense oligomer comprises a sequence of bases that specifically hybridizes to an exon 44 target region selected from the group consisting of H44A(−

07+15), H44A(−

08+15), H44A(−

06+15), H44A(−

08+17), H44A(−

07+17), and H44A(−

06+17), wherein the bases of said oligomer are linked to morpholino ring structures, and wherein said morpholino ring structures are joined by phosphorous-containing intersubunit linkages joining a morpholino nitrogen of one ring structure to a 5′

exocyclic carbon of an adjacent ring structure.

2. The antisense oligomer of claim 1, wherein the sequence is selected from the group consisting of SEQ ID NOs:

1 and 4-8.

3. The antisense oligomer of claim 1, which is about 20 to 30 nucleotides in length.

4. The antisense oligomer of claim 1, which is about 22 to 28 nucleotides in length.

5. The antisense oligomer of claim 2, wherein the sequence consists of a sequence selected from SEQ ID NO:

1 and 4-8.

6. The antisense oligomer of claim 1, wherein the oligomer does not activate RNase H.

7. The antisense oligomer of claim 1, wherein the oligomer is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligomer.

8. The antisense oligomer of claim 7, wherein the oligomer is chemically linked to a polyethylene glycol molecule.

9. The antisense oligomer of claim 1, wherein the antisense oligomer is conjugated to an arginine-rich peptide.

10. The antisense oligomer of claim 9, wherein the arginine-rich peptide comprises a sequence selected from SEQ ID NOS:

24 to 39.

11. The antisense oligomer of claim 1, comprising morpholino ring structures joined by substantially uncharged phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one ring structure to a 5′

exocyclic carbon of an adjacent ring structure.

12. The antisense oligomer of claim 11, wherein 5%-35% of the linkages is positively charged.

13. The antisense oligomer of claim 1, wherein the intersubunit linkages are uncharged and interspersed with linkages that are positively charged at physiological pH, wherein the total number of positively charged linkages is between 2 and no more than half of the total number of linkages.

14. The antisense oligomer of claim 1, comprising morpholino ring structures and phosphorodiamidate intersubunit linkages.

17. A composition comprising the antisense oligomer of claim 1 any of the preceding claims and a pharmaceutically acceptable carrier.

18. The composition of claim 17 for use in the treatment of muscular dystrophy.

19. The composition of claim 18, wherein the muscular dystrophy is Duchenne'"'"'s muscular dystrophy (DMD).

20. The composition of claim 18, wherein the muscular dystrophy is Becker'"'"'s muscular dystrophy (BMD).

15. The antisense oligomer are modified with a pendant cationic group.

16. An antisense oligomer selected from the group consisting of:

21. A composition comprising the antisense oligomer of claim 16 and a pharmaceutically acceptable carrier.