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. An antisense oligonucleotide 12 to 35 nucleotides in length comprising at least 12 consecutive nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs 54-65, wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage or sugar moiety, and wherein said antisense oligonucleotide has at least at least 95% complementarity to SEQ ID NO: 4.
2. The antisense oligonucleotide of claim 1 , wherein said antisense oligonucleotide has at least at least 100% complementarity to SEQ ID NO: 4.
3. The antisense oligonucleotide of claim 1 comprising a chimeric oligonucleotide having a gap segment positioned between 5′ and 3′ wing segments.
4. The antisense oligonucleotide of claim 3 , wherein the gap segment of the chimeric oligonucleotide is comprised of 2′-deoxynucleotides and the wing segments are comprised of nucleotides having modified sugar moieties.
5. The antisense oligonucleotide of claim 4 , wherein the modified sugar moiety is 2′-OMe or a bicyclic nucleic acid.
6. The antisense oligonucleotide of claim 3 , wherein the gap segment of the chimeric oligonucleotide consists of ten 2′-deoxynucleotides and each wing segment consists of five 2′-O-methoxyethyl-modified nucleotides.
7. The antisense oligonucleotide of claim 6 , wherein said antisense oligonucleotide is 20 nucleotides in length.
8. The antisense oligonucleotide of claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
9. The antisense oligonucleotide of claim 1 , wherein the each cytosine is a 5-methylcytosine.
10. The antisense oligonucleotide of claim 1 , wherein said oligonucleotide is 17 to 25 nucleotides in length.
11. The antisense oligonucleotide of claim 1 , wherein said oligonucleotide is 19 to 23 nucleotides in length.
12. The antisense oligonucleotide of claim 1 , wherein said oligonucleotide is 20 nucleotides in length.
13. A pharmaceutical composition comprising an antisense oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.
14. The antisense oligonucleotide of claim 1 , wherein said nucleotide sequence is selected from the group consisting of SEQ ID NOs: 55 and 60.
15. The antisense oligonucleotide of claim 14 , wherein said antisense oligonucleotide has at least at least 95% complementarity to SEQ ID NO: 4.
16. The antisense oligonucleotide of claim 14 , wherein said antisense oligonucleotide has at least at least 100% complementarity to SEQ ID NO: 4.
17. The antisense oligonucleotide of claim 14 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.
18. The antisense oligonucleotide of claim 14 comprising a chimeric oligonucleotide having a gap segment positioned between 5′ and 3′ wing segments.