Modulation of alpha synuclein expression
Disclosed herein are antisense compounds and methods for decreasing alpha-synuclein mRNA and protein expression. Also disclosed herein are methods for treating, preventing, and ameliorating neurodegenerative diseases in an individual in need thereof.
1. A modified, single-stranded oligonucleotide consisting of 12 to 30 linked nucleosides comprising a nucleobase sequence that is complementary to at least 8 contiguous nucleobases of nucleobases 236-301 of SEQ ID NO: 1; and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1 and wherein at least one nucleoside of the modified oligonucleotide comprises a 5-methylcytosine.
2. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to SEQ ID NO: 1.
3. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
4. The modified oligonucleotide of claim 3 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
5. The modified oligonucleotide of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
6. The modified oligonucleotide of claim 5 , wherein the modified sugar is a bicyclic sugar.
7. The modified oligonucleotide of claim 6 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge.
8. The modified oligonucleotide of claim 5 , comprising at least one tetrahydropyran modified nucleoside wherein a tetrahydropyran ring replaces the furanose ring.
9. The modified oligonucleotide of claim 8 , wherein each of the at least one tetrahydropyran modified nucleoside has the structure:
wherein Bx is an optionally protected heterocyclic base moiety.
10. The modified oligonucleotide of claim 5 , wherein the modified sugar comprises a 2′-O-methoxyethyl group.
11. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxy nucleosides;
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, wherein each nucleoside of each wing segment comprises a modified sugar.
12. The modified oligonucleotide of claim 11 , 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; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.
13. A compound comprising a single-stranded modified oligonucleotide consisting of at least 12 contiguous nucleobases of a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID Nos: 11-16, wherein at least one nucleoside of the modified oligonucleotide comprises a 5-methylcytosine.
14. The modified oligonucleotide of claim 1 , wherein the nucleobase sequence comprises a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID Nos: 11-16.
15. The modified oligonucleotide of claim 1 , wherein the nucleobase sequence consists of a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID Nos: 11-16.