Inhibiting or downregulating glycogen synthase by creating premature stop codons using antisense oligonucleotides

Patent metadata

Field	Value
Publication number	US-11801311-B2
Application number	US-202016867261-A
Country	US
Kind code	B2
Filing date	May 5, 2020
Priority date	May 23, 2014
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

The present disclosure relates to antisense oligonucleotides (AONs) for modulating the expression of glycogen synthase. AONs of the present disclosure may be useful in treating diseases associated with the modulation of the expression of the enzyme glycogen synthase, such as Pompe disease. Also provided by the present disclosure are compositions comprising AONs, as well as methods of down regulating mRNA coding for glycogen synthase, methods for reducing glycogen synthase in skeletal and cardiac muscle, and methods for treating Pompe disease.

First claim

What is claimed is:

1. A method of down regulating mRNA coding for glycogen synthase comprising administering an effective amount of an antisense oligonucleotide to an animal, wherein the antisense oligonucleotide comprises SEQ ID NO:58, 59, or 60, and wherein the hybridization of the antisense oligonucleotide to the nucleic acid sequence encoding for glycogen synthase induces exon skipping.

2. The method of claim 1 , wherein the antisense oligonucleotide is a phosphorodiamidate morpholino oligo (PMO).

3. The method of claim 1 , wherein the antisense oligonucleotide is a PMO linked to a cell penetrating peptide (CPP).

4. The method of claim 1 , wherein the antisense oligonucleotide is selected from an oligonucleotide comprising subunits of one of Formula I-VI:

wherein B in each of Formula I-VI is a nucleotide base.

5. The method of claim 1 , wherein the effective amount ranges from 5 to 500 mg per dose.

6. The method of claim 1 , wherein the compound is administered intravenously.

7. The method of claim 1 , wherein the down regulation of mRNA coding for glycogen synthase occurs in skeletal and cardiac muscle.

8. A method for reducing glycogen synthase in skeletal and cardiac muscle comprising administering to an animal an effective amount of an antisense oligonucleotide, wherein the antisense oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NO:58, 59, and 60, and wherein the hybridization of the antisense oligonucleotide to the nucleic acid sequence encoding for glycogen synthase induces exon skipping.

9. A method for treating Pompe disease comprising administering to an animal an effective amount of an antisense oligonucleotide, wherein the antisense oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NOs:58, 59, and 60, and wherein the hybridization of the antisense oligonucleotide to the nucleic acid sequence encoding for glycogen synthase induces exon skipping.

10. The method of claim 1 , wherein the antisense oligonucleotide comprises SEQ ID NO:58.

11. The method of claim 1 , wherein the antisense oligonucleotide comprises SEQ ID NO:59.

12. The method of claim 1 , wherein the antisense oligonucleotide comprises SEQ ID NO:60.

13. The method of claim 8 , wherein the antisense oligonucleotide comprises SEQ ID NO:58.

14. The method of claim 8 , wherein the antisense oligonucleotide comprises SEQ ID NO:59.

15. The method of claim 8 , wherein the antisense oligonucleotide comprises SEQ ID NO:60.

16. The method of claim 9 , wherein the antisense oligonucleotide comprises SEQ ID NO:58.

17. The method of claim 9 , wherein the antisense oligonucleotide comprises SEQ ID NO:59.

18. The method of claim 9 , wherein the antisense oligonucleotide comprises SEQ ID NO:60.

Assignees

• Genzyme Corp

Inventors

• Nelson Carol A
• Wentworth Bruce M
• Scheule Ronald K
• Weeden Timothy E
• Clayton Nicholas P

Classifications

• A61K48/005 Primary

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title

• C12N15/113

  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 title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C12Y204/01011 Primary

  Glycogen(starch) synthase (2.4.1.11) · CPC title

• C12N2310/11

  Antisense · CPC title