Compositions and their uses directed to huntingtin
Disclosed herein are compounds, compositions and methods for modulating the expression of huntingtin in a cell, tissue or animal. Further provided are methods of slowing or preventing Huntington's Disease (HD) progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntington's Disease (HD) in an individual susceptible to Huntington's Disease (HD). Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.
1. A compound comprising a single-stranded, modified oligonucleotide consisting of 12 to 35 linked nucleosides having a nucleobase sequence comprising at least 8 consecutive nucleobases of SEQ ID NO: 125, wherein said oligonucleotide is at least 90% complementary to SEQ ID NO: 4.
2. The compound of claim 1 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
3. The compound of claim 2 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
4. The compound or claim 1 , wherein at least one nucleoside comprises a modified sugar.
5. The compound of claim 4 , wherein at least one modified sugar is a bicyclic sugar.
6. The compound of claim 4 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl.
7. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
8. The compound of claim 7 , wherein the modified nucleobase is a 5-methylcytosine.
9. The compound of claim 1 , comprising a chimeric oligonucleotide having a gap segment positioned between 5′ and 3′ wing segments.
10. The compound of claim 9 , wherein the gap segment of the chimeric oligonucleotide consists often 2′-deoxynucleotides and each wing segment consists of five 2′-O-methoxyethyl-modified nucleotides.
11. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a. a gap segment consisting of linked deoxynucleosides;
b. a 5′ wing segment consisting of linked nucleosides:
c. a 3′ wing segment consisting of 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.
12. The compound of claim 11 , wherein the 5′ wing segment and the 3′ wing segment each consist of five linked nucleosides.
13. The compound of claim 12 , wherein at least one of the internucleoside linkages of the 5′ wing segment is a phosphorothioate linkage.
14. The compound of claim 12 , wherein at least one of the internucleoside linkages of the 3′ wing segment is a phosphorothioate linkage.
15. The compound of claim 12 , wherein at least one of the internucleoside linkages of the 5′ wing segment and at least one of the internucleoside linkages of the 3′ wing segment is a phosphorothioate linkage.
16. The compound of claim 15 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
17. The compound of claim 12 , wherein each of the internucleoside linkages of the 5′ wing segment is a phosphorothioate linkage.
18. The compound of claim 12 , wherein each of the internucleoside linkages of the 3′ wing segment is a phosphorothioate linkage.
19. The compound of claim 12 , wherein each of the internucleoside linkages of the 5′ wing segment and each of the internucleoside linkages of the 3′ wing segment is a phosphorothioate linkage.
20. The compound of claim 19 , wherein the modified oligonucleotide consists of 18 linked nucleosides.
21. The compound of claim 19 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
22. The compound of claim 11 , wherein the modified oligonucleotide comprises:
a. a gap segment consisting of ten linked deoxynucleosides;
b. a 5′ wing segment consisting of five linked nucleosides;
c. a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each cytidine residue of the modified oligonucleotide is a 5-methylcytidine; and wherein each internucleoside linkage of the gap segment, at least one of the internucleoside linkages of the 5′ wing segment, and at least one of the internucleoside linkages of the 3′ wing segment is a phosphorothioate linkage.
23. The compound of claim 22 , wherein each internucleoside linkage is a phosphorothioate linkage.
24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent.
25. The compound of claim 1 , wherein the modified oligonucleotide consists of 17-25 linked nucleosides.
26. The compound of claim 25 , wherein the modified oligonucleotide comprises at least 12 consecutive nucleobases of SEQ ID NO: 125.