Antisense Oligonucleotides

• US 20120202752A1
• Filed: 02/08/2012
• Published: 08/09/2012
• Est. Priority Date: 02/08/2011
• Status: Active Grant

• Current Assignee: Charlotte Mecklenburg Hospital Authority
• Original Assignee: Charlotte Mecklenburg Hospital Authority
• Inventors: Lu, Qi Long
• Granted Patent: US 9,078,911 B2
• Time in Patent Office: Days
• US Class Current: 514/20.9
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• 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: 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 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

Embodiments of the present invention are directed generally to antisense compounds and compositions for the treatment of muscular dystrophy, and in particular, Duchenne muscular dystrophy (DMD). In one embodiment, the invention is directed to antisense oligonucleotide molecules, pharmaceutical compositions and formulations comprising antisense oligonucleotide molecules, and methods of treating muscular dystrophy related diseases and disorders wherein the antisense oligonucleotide molecules comprises a base sequence selected from the group consisting of SEQ ID NO: 5-8, 10, 12, 14, 16, 24, 27, 28, 34, 35, 37, 40, 42, 44-46, 79, 97, 100, 101, and 116, and combinations thereof.

Claims

1. An antisense oligonucleotide molecule for treating DMD, the antisense oligonucleotide molecule comprising a base sequence selected from the group consisting of:

2. The antisense oligonucleotide molecule according to claim 1, wherein the exon of the dystrophin gene at which exon skipping is caused is selected from the group consisting of exon 43, 45, 50, 51, and 53.

3. The antisense oligonucleotide molecule according to claim 1, wherein the antisense oligonucleotide molecule is conjugated to or complexed with a distinct chemical entity.

4. The antisense oligonucleotide molecule according to claim 1, wherein the antisense oligonucleotide molecule is a phosphorodiamidate morpholino oligonucleotide (PMO).

5. The antisense oligonucleotide molecule according to claim 1, wherein the antisense oligonucleotide molecule is an oligomer which is capable to bind to its complementary RNA sequence.

6. The antisense oligonucleotide molecule according to claim 1, wherein the antisense oligonucleotide molecule includes one to two additional nucleotide bases at either end an end thereof, or a deletion of one to two nucleotide bases at end of a sequence, and wherein the one to two nucleotide bases can be complementary and/or not complementary to its target sequence.

7. A pharmaceutical composition for treating DMD, the composition comprising an antisense oligonucleotide molecule according to claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

8. A pharmaceutical composition comprising

an antisense oligonucleotide conjugated with a polymer to enhance the delivery of antisense oligonucleotide and antisense effect, wherein the antisense oligonucleotide is selected from the group consisting of

9. The composition of claim 8, wherein the antisense oligonucleotide comprises a morpholino oligomer or a PNA oligomer having from about 15 to 40 base pairing units (monomers).

10. The composition of claim 8, wherein the morpholino oligomer comprises a phosphorodiamidate-linked morpholino oligomer.

11. The composition of claim 8, wherein the polymer is a peptide.

12. The composition of claim 8, wherein the polymer is a cationic polymer.

13. The composition of claim 8, wherein the polymer is dendrimeric octaguanindine polymer.

14. A method of treating muscular dystrophy in a subject, comprising administering to the subject an effective amount of an antisense oligonucleotide molecule selected from the group consisting of

15. The method of claim 14, wherein the muscular dystrophy is Duchenne'"'"'s muscular dystrophy (DMD).

16. The method of claim 14, wherein the muscular dystrophy is Becker muscular dystrophy (BMD).

17. The method of claim 14, wherein the sequence is selected from the group consisting SEQ ID NOS:

5, 6, 7, 8, 10, 12, 14, 16 and 24 and the exon is exon 43.

18. The method of claim 14, wherein the sequence is selected from the group consisting SEQ ID NOS:

27, 28, 34, 35, 37, 40, 42, 44, 45, and 46 and the exon is exon 45.

19. The method of claim 14, wherein the sequence is selected from the group consisting SEQ ID NOS:

79, and 97, and the exon is exon 50.

20. The method of claim 14, wherein the sequence selected from the group consisting SEQ ID NOS:

100 and 101, and the exon is exon 51.

21. The method of claim 14, wherein the sequence is SEQ ID NO. 116 and the exon is exon 53.