Compositions for modulating Ataxin 2 expression
Disclosed herein are antisense compounds and methods for decreasing Ataxin 2 mRNA and protein expression. Such methods, compounds, and compositions 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), amyotropic sclerosis (ALS), and parkinsonism.
1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a region of at least 12 contiguous nucleobases which is 90% complementary to an equal length region of nucleobases 606-656 of SEQ ID NO:1, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.
2. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90%, at least 95% or 100% complementary to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.
3. The compound of claim 2 , consisting of a single-stranded modified oligonucleotide.
4. The compound of claim 2 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
5. The compound of claim 4 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
6. The compound of claim 4 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The compound of claim 5 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.
8. The compound of claim 5 , wherein at least one internucleoside linkage is a phosphorothioate linkage and at least one internucleoside linkage is a phosphodiester linkage.
9. The compound of claim 2 , wherein at least one nucleoside comprises a modified nucleobase.
10. The compound of claim 9 , wherein the modified nucleobase is a 5-methylcytosine.
11. The compound of claim 2 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
12. The compound of claim 11 , wherein the at least one modified sugar is a bicyclic sugar.
13. The compound of claim 12 , wherein the bicyclic sugar comprises a 4′-CH(R)—O-2′ bridge wherein R is, independently, H, C 1 -C 12 alkyl, or a protecting group.
14. The compound of claim 13 , wherein R is methyl.
15. The compound of claim 13 , wherein R is H.
16. The compound of claim 11 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group.
17. The compound of claim 2 , wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
18. The compound of claim 2 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
19. A composition comprising the compound of claim 1 and at least one of a pharmaceutically acceptable carrier or diluent.
20. The composition of claim 19 , wherein the modified oligonucleotide of the compound is a sodium salt.
21. A compound comprising a modified oligonucleotide consisting of 12 to 30 nucleosides and having a nucleobase sequence comprising at least 12 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11, 12, 13, 92, and 93, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.
22. The compound of claim 21 , consisting of a single-stranded modified oligonucleotide.
23. The compound of claim 21 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
24. The compound of claim 23 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
25. The compound of claim 23 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
26. The compound of claim 24 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.
27. The compound of claim 24 , wherein at least one internucleoside linkage is a phosphorothioate linkage and at least one internucleoside linkage is a phosphodiester linkage.
28. The compound of claim 21 , wherein at least one nucleoside comprises a modified nucleobase.
29. The compound of claim 28 , wherein the modified nucleobase is a 5-methylcytosine.
30. The compound of claim 21 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
31. The compound of claim 30 , wherein the at least one modified sugar is a bicyclic sugar.
32. The compound of claim 31 , wherein the bicyclic sugar comprises a 4′-CH(R)—O-2′ bridge wherein R is, independently, H, C 1 -C 12 alkyl, or a protecting group.
33. The compound of claim 32 , wherein R is methyl.
34. The compound of claim 32 , wherein R is H.
35. The compound of claim 30 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group.
36. The compound of claim 21 , wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
37. The compound of claim 21 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
38. A composition comprising the compound of claim 21 and at least one of a pharmaceutically acceptable carrier or diluent.
39. The composition of claim 38 , wherein the modified oligonucleotide of the compound is a sodium salt.