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 compound comprising a single-stranded modified oligonucleotide, wherein the single-stranded modified oligonucleotide is a gapmer consisting of a 5′ wing segment, a central gap segment, and a 3′ wing segment, wherein:
the 5′ wing segment consists of five linked nucleosides,
the central gap segment consists of ten linked deoxynucleosides, and the 3′ wing segment consists of five linked nucleosides,
wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein the single-stranded modified oligonucleotide has the nucleobase sequence of 5′-CTCAGTAACATTGACACCAC-3′ (SEQ ID NO: 22), wherein each cytosine is a 5-methylcytosine, and wherein each internucleoside linkage of the single-stranded modified oligonucleotide is either a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage; and
wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, the internucleoside linkage connecting the central gap segment to the 5′ wing segment is a phosphorothioate linkage, the internucleoside linkage connecting the central gap segment to the 3′ wing segment is a phosphorothioate linkage, the 5′-most internucleoside linkage of the 5′ wing segment is a phosphorothioate linkage, and the 3′-most internucleoside linkage of the 3′ wing segment is a phosphorothioate linkage; and the remaining internucleoside linkages are phosphodiester linkages.
2. The compound of claim 1 , consisting of the single-stranded modified oligonucleotide.
3. The compound of claim 1 , consisting of the single-stranded modified oligonucleotide covalently linked to a conjugate group.
4. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.
5. The compound of claim 4 , wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
7. The pharmaceutical composition of claim 6 , wherein the compound consists of the single-stranded modified oligonucleotide.
8. The pharmaceutical composition of claim 6 , wherein the compound consists of the single-stranded modified oligonucleotide covalently linked to a conjugate group.
9. The pharmaceutical composition of claim 6 , wherein the compound is a pharmaceutically acceptable salt.
10. A pharmaceutical composition consisting essentially of the compound of claim 1 and PBS.
11. A method for reducing huntingtin mRNA levels in an animal, the method comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of claim 6 .
12. The method of claim 11 , wherein the single-stranded modified oligonucleotide covalently linked to a conjugate group.
13. The method of claim 11 , wherein the compound is a pharmaceutically acceptable salt.
14. The method of claim 13 , wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.