EXON SKIPPING COMPOSITIONS FOR TREATING MUSCULAR DYSTROPHY

• US 20180016574A1
• Filed: 02/13/2017
• Published: 01/18/2018
• 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
• Application Number:
  US15/431,468
• Publication Number:
  US 20180016574A1
• Time in Patent Office: Days
• 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 oligonucleotide of 20 to 50 bases in length comprising at least 10 consecutive bases of a sequence selected from the group consisting of:

SEQ ID NOs;

1-7, wherein the oligonucleotide specifically hybridizes to an exon 44 target region of the human dystrophin pre-mRNA, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide induces exon 44 skipping, and wherein thymine bases are optionally uracil bases;

or a pharmaceutically acceptable salt thereof.

2. The antisense oligonucleotide of claim 1, comprising a base sequence selected from the group consisting of SEQ ID NOs:

1-7.

3. The antisense oligonucleotide of claim 1, consisting of a base sequence selected from the group consisting of SEQ ID NOs:

1-7.

15. The antisense oligonucleotide of claim 3, wherein the oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide.

17. The antisense oligonucleotide of claim 15, wherein the oligonucleotide is chemically linked to a polyethylene glycol moiety.

38. A pharmaceutical composition, comprising an antisense oligonucleotide of claim 1, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

39. A method of treating Duchenne muscular dystrophy in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 38.

4-14. -14. (canceled)

16. (canceled)

18. An antisense oligonucleotide of 20 to 50 bases in length comprising at least 10 consecutive bases of a base sequence complementary to an exon 44 target region of the human dystrophin pre-mRNA designated as an annealing site selected from the group consisting of:

H44A(−

07+17), H44A(−

07+20), H44A(−

07+22), H44A(+77+101), H44A(+64+91), H44A(+62+89), and H44A(+62+85), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide induces exon 44 skipping;

or a pharmaceutically acceptable salt thereof.

19. The antisense oligonucleotide of claim 18, wherein the antisense oligonucleotide is 20 to 30 bases in length.

20. The antisense oligonucleotide of claim 19, wherein in the base sequence the thymine bases are uracil bases.

32. The antisense oligonucleotide of claim 20, wherein the oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide.

34. The antisense oligonucleotide of claim 32, wherein the oligonucleotide is chemically linked to a polyethylene glycol moiety.

43. A pharmaceutical composition, comprising an antisense oligonucleotide of claim 18, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

44. A method of treating Duchenne muscular dystrophy in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 43.

21-31. -31. (canceled)

33. (canceled)

35-37. -37. (canceled)

40-42. -42. (canceled)