Modulation of huntingtin expression
Provided herein are methods, compounds, and compositions for reducing expression of huntingtin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate Huntington's disease, or a symptom thereof.
1. A single-stranded modified oligonucleotide consisting of 20 linked nucleosides and having:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides; and
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 the nucleobase sequence of the oligonucleotide consists of the sequence recited in SEQ ID NO: 28,
or a pharmaceutically acceptable salt thereof.
2. The single-stranded modified oligonucleotide of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
3. The single-stranded modified oligonucleotide of claim 2 , wherein the modified nucleobase is a 5-methylcytosine.
4. The single-stranded modified oligonucleotide of claim 1 , wherein each cytosine is a 5-methylcytosine.
5. The single-stranded modified oligonucleotide of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
6. The compound of claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The single-stranded modified oligonucleotide of claim 4 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
8. The compound of claim 4 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
9. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 1 and at least one pharmaceutically acceptable carrier or diluent.
10. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 4 and at least one pharmaceutically acceptable carrier or diluent.
11. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 6 and at least one pharmaceutically acceptable carrier or diluent.
12. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 8 and at least one pharmaceutically acceptable carrier or diluent.
13. The single-stranded modified oligonucleotide of claim 1 , which is capable of inhibiting huntingtin expression.
14. The single-stranded modified oligonucleotide of claim 4 , which is capable of inhibiting huntingtin expression.
15. The single-stranded modified oligonucleotide of claim 6 , which is capable of inhibiting huntingtin expression.
16. The single-stranded modified oligonucleotide of claim 8 , which is capable of inhibiting huntingtin expression.