Modulation of dystrophia myotonica-protein kinase (DMPK) expression

Patent metadata

Field	Value
Publication number	US-9765338-B2
Application number	US-201514814174-A
Country	US
Kind code	B2
Filing date	Jul 30, 2015
Priority date	Jul 19, 2010
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of a DMPK mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathy in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate type 1 myotonic dystrophy, or a symptom thereof.

First claim

What is claimed is:

1. A method of treating an animal having type 1 myotonic dystrophy comprising administering to the animal a therapeutically effective amount of a compound comprising an oligonucleotide consisting of 10 to 30 linked nucleosides targeted to a DMPK nucleic acid, wherein the oligonucleotide has a nucleobase sequence that is at least 90% complementary to a non-CUG repeat region of SEQ ID NO: 1 or SEQ ID NO: 2 as measured over the entirety of the oligonucleotide, wherein the compound reduces myotonia or reduces spliceopathy in the animal.

2. The method of claim 1 , wherein the animal is a human.

3. The method of claim 2 , wherein myotonia is reduced by at least 25%.

4. The method of claim 3 , wherein myotonia is reduced in any of the quadriceps muscle, the gastrocnemius muscle, or the tibialis anterior muscle.

5. The method of claim 2 , wherein the oligonucleotide has a nucleobase sequence that is 100% complementary to SEQ ID NO: 1 or SEQ ID NO: 2.

6. The method of claim 1 , wherein the oligonucleotide is a modified oligonucleotide.

7. The method of claim 6 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.

8. The method of claim 7 , wherein the single-stranded modified oligonucleotide is a gapmer.

9. The method of claim 7 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified linkage.

10. The method of claim 9 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

11. The method of claim 9 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

12. The method of claim 11 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

13. The method of claim 9 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage and at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.

14. The method of claim 7 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase.

15. The method of claim 14 , wherein the modified nucleobase is a 5-methylcytosine.

16. The method of claim 7 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

17. The method of claim 16 , wherein the modified sugar is a bicyclic sugar.

18. The method of claim 17 , wherein the bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein the chemical bridge is selected from: 4′—CH(R)—O—2′ and 4′—(CH 2 ) 2 —O—2′, wherein R is independently H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.

19. The method of claim 18 , wherein the chemical bridge is 4′—CH(R)—O—2′ and wherein R is methyl.

20. The method of claim 18 , wherein the chemical bridge is 4′—CH(R)—O—2′ and wherein R is H.

21. The method of claim 18 , wherein the chemical bridge is 4′—CH(R)—O—2′ and wherein R is —CH 2 —O—CH 3 .

22. The method of claim 16 , wherein the modified sugar comprises a 2′—O-methoxyethyl group.

23. The method of claim 1 , wherein the compound comprises the oligonucleotide covalently linked to a conjugate group.

24. The method of claim 1 , wherein the oligonucleotide is a salt.

Assignees

• Isis Pharmaceuticals Inc
• Univ Rochester
• Ionis Pharmaceuticals Inc

Inventors

• Bennett C Frank
• Freier Susan M
• Macleod Robert A
• Pandey Sanjay K
• Thornton Charles A
• Wheeler Thurman
• Cheng Seng H
• Leger Andrew
• Wentworth Bruce M

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P21/04

  for myasthenia gravis · CPC title