Methods for modulating Ataxin 2 expression

Patent metadata

Field	Value
Publication number	US-10006027-B2
Application number	US-201515127352-A
Country	US
Kind code	B2
Filing date	Mar 19, 2015
Priority date	Mar 19, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

Disclosed herein are methods for decreasing Ataxin 2 mRNA and protein expression. Such methods are useful to treat, prevent, or ameliorate Ataxin 2 associated diseases, disorders, and conditions. Such Ataxin 2 associated diseases include spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and parkinsonism. Provided are methods for reducing expression of Ataxin 2 (ATXN2) mRNA and protein in an animal. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases, including spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and parkinsonism by inhibiting expression of Ataxin 2 in an animal.

First claim

What is claimed is:

1. A method comprising administering a single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the modified oligonucleotide is at least 90% complementary to an Ataxin 2 nucleic acid to an animal for treating an Ataxin 2 associated disease, wherein the modified oligonucleotide is not complementary to a CAG repeat expansion in the Ataxin 2 nucleic acid.

2. A method comprising:
identifying an animal having an Ataxin 2 associated disease; and
administering a single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the modified oligonucleotide is at least 90% complementary to an Ataxin 2 nucleic acid, wherein the modified oligonucleotide is not complementary to a CAG repeat expansion in the Ataxin 2 nucleic acid.

3. The method of claim 1 , wherein the Ataxin 2 associated disease is a neurodegenerative disease.

4. The method of claim 3 , wherein the neurodegenerative disease is spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), or parkinsonism.

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

6. The method of claim 5 , wherein the administering is parenteral administration.

7. The method of claim 6 , wherein the parenteral administration is any of intrathecal administration or intracerebroventricular administration.

8. The method of claim 6 , wherein the administering distributes the antisense compound to the Purkinje cells.

9. The method of claim 6 , wherein the administering improves rotarod performance.

10. The method of claim 9 , wherein rotarod performance is improved by 10 percent, 15 percent, or 20 percent.

11. The method of claim 6 , wherein the administering improves motor function.

12. The method of claim 11 , wherein motor function is improved by 10 percent, 15 percent, or 20 percent.

13. The method of claim 5 , wherein at least one symptom of an Ataxin 2 associated disease is ameliorated, treated, prevented, or slowed.

14. The method of claim 1 , wherein the Ataxin 2 nucleic acid has the sequence of any of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

15. The method of claim 14 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

16. The method of claim 15 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

17. The method of claim 16 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

18. The method of claim 14 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

19. The method of claim 18 , wherein the modified nucleobase is a 5-methylcytosine.

20. The method of claim 14 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

21. The method of claim 20 , wherein the at least one modified sugar is a bicyclic sugar.

22. The method of claim 21 , wherein the bicyclic sugar comprises a chemical bridge between the 2′ and 4′ position of the sugar, wherein the chemical bridge is selected from: 4′-CH 2 -O-2′; 4′-CH(CH 3 )-O-2′; 4′-(CH 2 ) 2 -O-2′; and 4′-CH 2 -N(R)-O-2′ wherein R is, independently, H, C 1 -C 12 alkyl, or a protecting group.

23. The method of claim 20 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group.

24. The method of claim 14 , wherein the modified oligonucleotide is a gapmer.

25. The method of claim 1 , wherein the modified oligonucleotide is at least 95% complementary to an Ataxin 2 nucleic acid.

26. The method of claim 1 , wherein the modified oligonucleotide is at least 97% complementary to an Ataxin 2 nucleic acid.

27. The method of claim 1 , wherein the modified oligonucleotide is 100% complementary to an Ataxin 2 nucleic acid.

28. The method of claim 2 , wherein the modified oligonucleotide is at least 95% complementary to an Ataxin 2 nucleic acid.

29. The method of claim 2 , wherein the modified oligonucleotide is at least 97% complementary to an Ataxin 2 nucleic acid.

30. The method of claim 2 , wherein the modified oligonucleotide is 100% complementary to an Ataxin 2 nucleic acid.

Assignees

• Ionis Pharmaceuticals Inc
• Univ Utah Res Found
• Univ Of Utah Reseach Foundation

Inventors

• Bennett C Frank
• Freier Susan M
• Pulst Stefan M
• Scoles Daniel R
• Hung Gene

Classifications

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title