Modulators of pnpla3 expression

Abstract

Embodiments of the present invention provide methods, compounds, and compositions that can be used to inhibit the expression of PNPLA3, and these methods, compounds, and compositions can be used to treat, prevent, or alleviate diseases associated with PNPLA3.

Claims

1. A compound comprising a modified oligonucleotide, the modified oligonucleotide having 16 nucleosides and having a nucleobase sequence comprising SEQ ID NO: 1089 or a pharmaceutically acceptable salt.

2. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modification selected from: at least one modified internucleotide link, at least one modified sugar, and at least one modified nucleobase.

3. The compound of claim 2, wherein the modified nucleoside linkage is a thiophosphate nucleoside linkage.

4. The compound of claim 2 or 3, wherein the modified sugar is a dicyclic sugar.

5. The compound of claim 4, wherein the dicyclic sugar is selected from the group consisting of: 4'-(CH2)-O-2' (LNA); 4'-(CH2)2-O-2' (ENA); and 4'-CH(CH3)-O-2' (cEt).

6. The compound of claim 2 or claim 3, wherein the modified sugar is 2'-O-methoxyethyl.

7. The compound of claim 2 or 3, wherein the modified nucleobase is 5-methylcytosine.

8. The compound of any one of claims 1-3, wherein the modified oligonucleotide comprises: A gap segment composed of linked deoxynucleosides; The 5' wing segment composed of linked nucleosides; And a 3' wing segment composed of linked nucleosides; wherein the notched segment is positioned adjacent to and between the 5' wing segment and the 3' wing segment, and wherein each nucleoside in each wing segment comprises a modified sugar.

9. The compound of any one of claims 1-3 further includes a conjugate group.

10. The compound of claim 9, wherein the conjugate group comprises a GalNAc cluster containing 1-3 GalNAc ligands.

11. The compound of claim 9, wherein the conjugate group is attached to the modified oligonucleotide at the 5'-end of the modified oligonucleotide.

12. The compound of claim 10, wherein the conjugate group is [missing information].

13. The compound of any one of claims 1-3, wherein the pharmaceutically acceptable sodium salt is a sodium salt.

14. The compound of any one of claims 1-3, wherein the pharmaceutically acceptable potassium salt is.

15. A composition comprising a compound as claimed in any one of claims 1-14 and a pharmaceutically acceptable carrier.

16. Use of a compound as claimed in any one of claims 1-14 or a composition as claimed in claim 15 for the preparation of a medicament for the treatment, prevention or relief of diseases associated with PNPLA3 in an individual.

17. As claimed in claim 16, wherein the disease is liver disease, NAFLD, hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.

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