Methods for modulating Ataxin 2 expression
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.
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.