Compositions and their uses directed to huntingtin
View Patent ↗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 progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntingtin's disease in an individual susceptible to Huntingtin's Disease. 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 modified oligonucleotide consisting of 20 to 35 linked nucleosides comprising all 20 nucleobases of SEQ ID NO: 118.
2. The compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
3. The compound of claim 1 , wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO: 4.
4. The compound of claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 4.
5. The compound of claim 2 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
6. The compound of claim 5 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The compound of claim 2 , wherein at least one nucleoside comprises a modified sugar.
8. The compound of claim 7 , wherein at least one modified sugar is a bicyclic sugar.
9. The compound of claim 7 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl.
10. The compound of claim 2 , wherein at least one nucleoside comprises a modified nucleobase.
11. The compound of claim 10 , wherein the modified nucleobase is a 5-methylcytosine.
12. The compound of claim 1 compound comprising a modified oligonucleotide 20 to 35 linked nucleotides in length, wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
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.
13. The compound of claim 12 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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 said modified oligonucleotide is a phosphorothioate linkage.
14. The compound of claim 13 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
15. The compound of claim 1 , wherein said modified oligonucleotide consists of 20 to 25 linked nucleosides.
16. The compound of claim 1 , wherein said modified oligonucleotide consists of 20 to 23 linked nucleosides.
17. The compound of claim 1 , wherein said modified oligonucleotide consists of 20 linked nucleosides.
18. The compound of claim 1 , wherein said modified oligonucleotide consists of a nucleobase sequence of SEQ ID NO: 118.
19. The compound of claim 1 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 118 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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 internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytidine residue of said modified oligonucleotide is a 5-methylcytidine.
20. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
21. The compound of claim 1 , wherein said modified oligonucleotide consists of a nucleobase sequence of SEQ ID NO: 118.
22. The composition of claim 20 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 118 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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 internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytidine residue of said modified oligonucleotide is a 5-methylcytidine.
23. A compound comprising a modified oligonucleotide consisting of 20 to 35 linked nucleosides comprising an at least 20 consecutive nucleobase portion complementary to nucleotides 4856-4875 of SEQ ID NO: 4, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO: 4.