Compositions for modulating C9ORF72 expression
Disclosed herein are compositions and methods for reducing expression of C9ORF72 mRNA and protein in an animal. Such methods are useful to treat, prevent, ameliorate, or slow progression of neurodegenerative diseases in an individual in need thereof.
1. A modified oligonucleotide according to the following formula:
or a salt thereof.
2. A modified oligonucleotide according to the following formula:
3. The modified oligonucleotide of claim 1 , which is a sodium salt of the formula.
4. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent or carrier.
5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).
6. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).
7. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent or carrier.
8. The pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).
9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).
10. A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent or carrier.
11. The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).
12. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).
13. A compound comprising a modified oligonucleotide, wherein the 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 four 2′-O-methoxyethyl nucleosides,
the central gap segment consists of eight β-D-deoxyribonucleosides, and
the 3′ wing segment consists of six 2′-O-methoxyethyl nucleosides;
wherein the modified oligonucleotide has the nucleobase sequence 5′-GCCCCTAGCGCGCGACTC-3′ (SEQ ID NO: 33), wherein each cytosine is a 5-methylcytosine; and wherein the internucleoside linkages of the modified oligonucleotide are, from 5′ to 3′, soosssssssssoooss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.
14. The compound of claim 13 , comprising the modified oligonucleotide covalently linked to a conjugate group.
15. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable diluent or carrier.
16. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).
17. The pharmaceutical composition of claim 15 , wherein the pharmaceutical composition consists essentially of the compound and phosphate-buffered saline (PBS).
18. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable diluent or carrier.
19. The pharmaceutical composition of claim 18 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).
20. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition consists essentially of the compound and phosphate-buffered saline (PBS).