Compounds and methods for reducing ATXN3 expression
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 mRNA in a cell or animal, and in certain instances reducing the amount of Ataxin-3 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to prevent or ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include SCA3.
1. An oligomeric compound comprising a modified oligonucleotide consisting of 18-30 linked nucleosides and having a nucleobase sequence comprising at least 17 contiguous nucleobases of any of SEQ ID NOs: 98-102, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
2. The oligomeric compound of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 95%, or is 100% complementary to the nucleobase sequence of SEQ ID NO: 1, when measured across the entire nucleobase sequence of the modified oligonucleotide.
3. The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside.
4. The oligomeric compound of claim 3 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
5. The oligomeric compound of claim 4 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
6. The oligomeric compound of claim 5 , wherein the bicyclic sugar moiety has a 2′-4′ bridge, wherein the 2′-4′ bridge is —O—CH 2 — or —O—CH(CH 3 )—.
7. The oligomeric compound of claim 3 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.
8. The oligomeric compound of claim 7 , wherein the non-bicyclic sugar moiety comprises a 2′-MOE group or a 2′-OMe group.
9. The oligomeric compound of claim 3 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate selected from morpholino and PNA.
10. The oligomeric compound of claim 1 , wherein the modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 1-5 linked 5′-region nucleosides;
a central region consisting of 6-10 linked central region nucleosides; and
a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein
each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.
11. The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
12. The oligomeric compound of claim 11 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.
13. The oligomeric compound of claim 11 , wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.
14. The oligomeric compound of claim 11 , wherein each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.
15. The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
16. The oligomeric compound of claim 15 , wherein the modified nucleobase is a 5-methylcytosine.
17. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 18-20 linked nucleosides.
18. The oligomeric compound of claim 1 , comprising a conjugate group comprising a conjugate moiety and a conjugate linker.
19. The oligomeric compound of claim 1 , wherein the oligomeric compound is a single-stranded oligomeric compound.
20. An oligomeric duplex comprising an oligomeric compound of claim 1 .
21. A modified oligonucleotide consisting of 18-30 linked nucleosides and having a nucleobase sequence comprising at least 17 contiguous nucleobases of any of SEQ ID NOs: 98-102, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
22. An oligomeric compound comprising a modified oligonucleotide consisting of 18-30 linked nucleosides and having a nucleobase sequence comprising a portion of at least 17 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 1091-1131 of SEQ ID NO: 1,
wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
23. A pharmaceutical composition comprising an oligomeric compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
24. A chirally enriched population of oligomeric compounds of claim 1 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
25. An oligomeric compound comprising a modified oligonucleotide consisting of 15-30 linked nucleosides and having a nucleobase sequence comprising at least 15 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 1091-1131 of SEQ ID NO: 1, wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to the nucleobase sequence of SEQ ID NO: 1 when measured across the entire nucleobase sequence of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.