ANTISENSE OLIGONUCLEOTIDES FOR INDUCING EXON SKIPPING AND METHODS OF USE THEREOF

• US 20130116310A1
• Filed: 12/26/2012
• Published: 05/09/2013
• Est. Priority Date: 06/28/2004
• Status: Abandoned Application

• Current Assignee: University of Western Australia
• Original Assignee: University of Western Australia
• Inventors: Wilton, Stephen Donald, Fletcher, Sue, McClorey, Graham
• Application Number:
  US13/727,415
• Publication Number:
  US 20130116310A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/3519 Fusion with another nucleic acid
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

An antisense molecule capable of binding to a selected target site to induce exon skipping in the dystrophin gene, as set forth in SEQ ID NO: 1 to 202.

Claims

1. An antisense molecule capable of binding to a selected target site to induce exon skipping in the dystrophin gene, as set forth in SEQ ID NO:

1 to 202.

2. An antisense molecule according to claim 1 capable of inducing exon skipping in exons 3, 4, 8, 10 to 16, 19 to 40, 42 to 44, 46, 47 and 50 to 53 of the dystrophin gene.

3. A combination of two or more antisense molecules according to claim 1 or 2 capable of binding to a selected target to induce exon skipping in the dystrophin gene.

4. A combination or two or more antisense molecules according to claim 3 selected from Table 1B.

5. A combination of two or more antisense molecules according to claim 1 or 2 joined together to form a “

weasel”

, wherein said weasel is capable of binding to a selected target to induce exon skipping in the dystrophin gene.

6. A combination of two or more antisense molecules according to claim 5 selected from Table 1C.

7. The antisense molecule according to any one of claims 1 to 6, capable of binding to a selected target site, wherein the target site is an mRNA splicing site selected from a splicer donor site, splice acceptor sites or exonic splicing enhancer elements.

8. A method of treating muscular dystrophy in a patient comprising administering to the patient a composition comprising an antisense molecule according to anyone of claims 1 to 6.

9. A pharmaceutical or therapeutic composition for the treatment of muscular dystrophy in a patient comprising (a) at least an antisense molecule according to any one of claims 1 to 6, and (b) one or more pharmaceutically acceptable carriers and/or diluents.

10. The composition according to claim 9, comprising about 20 nM to 600 nM of the antisense molecule.

11. The use of an antisense molecule according to any one of claims 1 to 6 for the manufacture of a medicament for modulation of muscular dystrophy.

12. An antisense molecule according to any one of claims 1 to 6 for use in antisense molecule based therapy.

13. An antisense molecule according to any one of claims 1 to 6 as herein before described with reference to the examples.

14. A kit comprising at least one antisense molecule according to any one of claims 1 to 6, a suitable carrier and instructions for its use.

15. An oligomer for ameliorating DMD, the oligomer comprising at least 25 contiguous bases of a base sequence selected from the group consisting of:

16. The oligomer according to claim 15, wherein the exon of the dystrophin gene at which exon skipping is caused is exon 53.

17. The oligomer according to claim 15, wherein the oligomer causes an exon skipping rate of at least 50%.

18. The oligomer according to claim 15, wherein the oligomer is between 25 and 35 bases in length.

19. The oligomer according to claim 15, wherein the oligomer is 30 bases in length.

20. The oligomer according to claim 15, wherein the oligomer is conjugated to or complexed with a distinct chemical entity.

21. The oligomer according to claim 15, wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO).

22. A vector for ameliorating DMD, the vector encoding an oligomer according to claim 15, wherein when introduced into a human cell the oligomer is expressed.

23. A pharmaceutical composition for ameliorating DMD, the composition comprising an oligomer according to claim 15 or a vector according to claim 22, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

24. A pharmaceutical composition according to claim 23 comprising a plurality of oligomers or vectors encoding oligomers, or a combination of the oligomers and vectors, wherein the oligomers and/or vectors in the pharmaceutical composition cause skipping in a plurality of exons.