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. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises a portion of at least 12 contiguous nucleobases, wherein the portion is complementary to:
(i) an equal length portion of nucleobases 1693-1767 of SEQ ID NO: 1;
(ii) an equal length portion of nucleobases 1789-1826 of SEQ ID NO: 1;
(iii) an equal length portion of nucleobases 1844-1887 of SEQ ID NO: 1;
(iv) an equal length portion of nucleobases 2291-2350 of SEQ ID NO: 1;
(v) an equal length portion of nucleobases 3082-3141 of SEQ ID NO: 1;
(vi) an equal length portion of nucleobases 3903-3946 of SEQ ID NO: 1;
(vii) an equal length portion of nucleobases 4005-4054 of SEQ ID NO: 1; or
(viii) an equal length portion of nucleobases 4429-4454 of SEQ ID NO: 1;
wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 29-35, 49, 50, 57-59, 63-66, 75, or 76, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
3. The oligomeric compound of claim 1 , wherein the modified oligonucleotide is at least 95% or is 100% complementary to an equal length portion of an Ataxin 2 RNA transcript.
4. The oligomeric compound of claim 3 , wherein the Ataxin-2 RNA transcript has the nucleobase sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.
5. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 12 to 25, 12 to 22, 13 to 30, 14 to 20, 14 to 30, 15 to 25, 15 to 30, 16 to 30, 17 to 30, 18 to 22, 18 to 30, 19 to 21, 19 to 30, or 20 to 30 linked nucleosides.
6. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
7. The oligomeric compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
8. The oligomeric compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
9. The oligomeric compound of claim 8 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
10. The oligomeric compound of claim 9 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
11. The oligomeric compound of claim 9 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
12. The oligomeric compound of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.
13. The oligomeric compound of claim 12 , wherein the modified nucleobase is a 5-methylcytosine.
14. The oligomeric compound of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar moiety.
15. The oligomeric compound of claim 14 , wherein the modified sugar moiety is a 2′-substituted sugar moiety.
16. The oligomeric compound of claim 14 , wherein the modified sugar moiety is a bicyclic sugar moiety.
17. The oligomeric compound of claim 16 , wherein the bicyclic sugar moiety comprises a 4′-CH(R)—O-2′ bridge wherein R is H, C 1 -C 12 alkyl, or a protecting group.
18. The oligomeric compound of claim 17 , wherein R is methyl.
19. The oligomeric compound of claim 17 , wherein R is H.
20. The oligomeric compound of claim 15 , wherein the modified sugar moiety is a 2′-O-methoxyethyl group.
21. The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxyribonucleosides;
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 moiety.
22. A pharmaceutical composition comprising the oligomeric compound of claim 1 or a salt thereof, and a pharmaceutically acceptable diluent.
23. The pharmaceutical composition of claim 22 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).