Selective antisense compounds and uses thereof
The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount, activity, or expression of the target nucleic acid in a cell. In certain embodiments, hybridization results in selective modulation of the amount, activity, or expression of a target Huntingtin gene or Huntingtin transcript in a cell.
1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of the nucleobase sequence recited in SEQ ID NO: 2, wherein the modified oligonucleotide has a sugar motif selected from ekek-d9-keke, kekk-d8-keke, ekkk-d8-kke, ekk-d8-kkke, ekekk-d8-keke, ekek-d8-kkeke, eekk-d8-kkeee, and eeekk-d8-kkee, wherein k is a cEt sugar moiety, e is a 2′-OCH 2 CH 2 OCH 3 ribosyl sugar moiety, and d is a 2′-deoxyribosyl sugar moiety.
2. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO. 1.
3. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 5.
4. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 6.
5. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 27.
6. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 28.
7. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 29.
8. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 30.
9. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 38.
10. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 39.
11. The compound of claim 1 , wherein the modified oligonucleotide has the nucleobase sequence recited in SEQ ID NO: 46.
12. The compound of claim 3 , wherein the modified oligonucleotide has a ekek-d9-keke sugar motif.
13. The compound of claim 4 , wherein the modified oligonucleotide has a kekk-d8-keke sugar motif.
14. The compound of claim 5 , wherein the modified oligonucleotide has a ekkk-d8-kke sugar motif.
15. The compound of claim 6 , wherein the modified oligonucleotide has a ekk-d8-kkke sugar motif.
16. The compound of claim 7 , wherein the modified oligonucleotide has a ekekk-d8-keke sugar motif.
17. The compound of claim 8 , wherein the modified oligonucleotide has a ekek-d8-kkeke sugar motif.
18. The compound of claim 9 , wherein the modified oligonucleotide has a eekk-d8-kkeee sugar motif.
19. The compound of claim 10 , wherein the modified oligonucleotide has a eekk-d8-kkeee sugar motif.
20. The compound of claim 11 , wherein the modified oligonucleotide has a eeekk-d8-kkee sugar motif.
21. The compound of claim 1 , comprising at least one phosphorothioate internucleoside linkage.
22. A method of ameliorating a symptom of Huntington's disease, comprising administering the compound of claim 1 to a subject in need thereof.
23. The compound of claim 1 , wherein the compound is conjugated.
24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.