Modulators of APOL1 expression
The present embodiments provide methods, compounds, and compositions useful for inhibiting APOL1 expression, which may be useful for treating, preventing, or ameliorating a disease associated with APOL1.
1. A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence SEQ ID NO: 1164, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the modified oligonucleotide consists of 16 to 30 linked nucleosides.
3. The compound of claim 2 , wherein the modified oligonucleotide consists of 16 linked nucleosides.
4. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, and/or at least one modified sugar, and/or at least one modified nucleobase.
5. The compound of claim 4 , wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
6. The compound of claim 4 , wherein the at least one modified sugar is a bicyclic sugar.
7. The compound of claim 6 , wherein the bicyclic sugar comprises a a 4′-CH 2 -O-2′ group or a 4′-CH(CH 3 )-O-2′ group or a 4′-(CH 2 ) 2 -O-2′ group.
8. The compound of claim 4 , wherein the at least one modified sugar comprises a 2′-O(CH) 2 -OCH 3 group or a 2′-O-CH 3 group.
9. The compound of claim 4 , wherein the at least one modified nucleobase is a 5-methylcytosine.
10. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of nine linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of four 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 cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage; wherein each cytosine is a 5-methylcytosine.
11. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a sodium salt.
12. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt.
13. A composition comprising the compound of claims 1 - 12 and a pharmaceutically acceptable carrier.
14. A method of inhibiting expression of APOL1 in a cell comprising contacting the cell with a compound according to claims 1 - 12 , thereby inhibiting expression of APOL1 in the cell.
15. The method of claim 14 , wherein the cell is in the kidney of an individual.