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 method of reducing expression of mutant huntingtin mRNA in a cell, comprising contacting a cell in the central nervous system of a subject with a modified oligonucleotide 12 to 35 nucleobases in length, wherein the modified oligonucleotide comprises at least 12 consecutive nucleobases of a nucleotide sequence selected from the group consisting of SEQ ID NOs 48-52, and wherein the modified oligonucleotide is 100% complementarity to SEQ ID NO. 4.
2. The method of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
3. The method of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.
4. The method of claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
5. The method of claim 1 , wherein at least one nucleoside comprises a modified sugar.
6. The method of claim 5 , wherein at least one modified sugar is a bicyclic sugar.
7. The method of claim 5 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl moiety.
8. The method of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
9. The method of claim 8 , wherein the modified nucleobase is a 5-methylcytosine.
10. The method of claim 1 , 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.
11. The method of claim 10 , 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; and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.
12. The method of claim 11 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
13. The method of claim 1 , wherein said modified oligonucleotide consists of 17 to 25 linked nucleosides.
14. The method of claim 1 , wherein said modified oligonucleotide consists of 19 to 23 linked nucleosides.
15. The compound of method of claim 1 , wherein said modified oligonucleotide consists of 20 linked nucleosides.
16. The method of claim 1 , wherein said modified oligonucleotide comprises a nucleobase sequence selected from the group consisting of SEQ ID NO: 49, 50, and 52.
17. The method of claim 11 , wherein said modified oligonucleotide comprises a nucleobase sequence selected from the group consisting of SEQ ID NO: 49, 50, and 52.