BIOMARKER OF PNPLA3 EXPRESSION

Abstract

The present disclosure relates to a novel biomarker for measuring PNPLA3 gene expression and methods of using the novel biomarker for treating, preventing, or ameliorating a disease associated with PNPLA3.

Claims

1. A method for the screening and/or diagnosis of a disease associated with PNPLA3 comprising measuring the CE 16:1/16:0 ratio in a patient in need of therapy of a disease associated with PNPLA3.

2. The method of claim 1, wherein the disease is chosen from liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transanimases, or hepatic fat accumulation in a patient having, or at risk of having, a liver disease associated with PNPLA3.

3. The method of claim 1, wherein the disease is NAFLD, hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.

4. The method of claim 1, wherein the patient in need thereof has a CE 16:1/16:0 ratio above 0.3.

5. The method of claim 4, wherein the patient in need thereof is administered a compound targeting PNPLA3 nucleic acid.

6. The method of claim 5, wherein the compound targeting PNPLA3 nucleic acid is chosen from ION 916333, ION 975616, ION 975613, ION975612, ION 916789, 916602, or salts thereof.

7. The method of claim 6, wherein the compound targeting PNPLA3 nucleic acid is chosen from ION 916333, ION 975616, or salts thereof.

8. A method of treating a disease associated with PNPLA3 in a patient in need thereof, comprising: a) identifying a patient with a CE 16:1/16:0 ratio above 0.3; and b) administering a compound targeting PNPLA3 nucleic acid to the patient.

9. The method of claim 8, wherein the disease is chosen from liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transanimases, or hepatic fat accumulation in a patient having, or at risk of having, a liver disease associated with PNPLA3.

10. The method of claim 8, wherein the disease is NAFLD, hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.

11. The method of claim 8, wherein the compound targeting PNPLA3 nucleic acid is chosen from ION 916333, ION 975616, ION 975613, ION975612, ION 916789, 916602, or salts thereof.

12. The method of claim 11, wherein the compound targeting PNPLA3 nucleic acid is chosen from ION 916333, ION 975616, or salts thereof.

Description

FIGURE LEGEND

[0028] FIG. 1 The CE 16:1/16:0 ratio measured in both plasma and liver of wild-type and 148M knock-in mice after PNPLA3 silencing

[0029] FIG. 2 The correlation between plasma CE 16:1/16:0 and liver PNPLA3 mRNA after a single dose of PNPLA3 ASO

EXAMPLES

[0030] Effects of PNPLA3 silencing with a potent liver-targeted GalNAc-conjugated antisense oligonucleotide (ASO), ION 975616, in both wild-type and 148M knock-in mice, on plasma and liver lipidomics were investigated. Cohorts of mice were fed either a steatogenic high-sucrose diet or a NASH diet high in fructose, trans-fatty acids and cholesterol to induce marked liver steatosis, inflammation and fibrosis. Plasma and liver lipid composition were investigated using a combination of UPLC-MS/MS and direct infusion (shotgun). The ratio between cholesteryl palmitoleate and cholesteryl palmitate (CE 16:1/16:0) was reduced in both plasma and liver after PNPLA3 silencing (FIG. 1). This effect was independent of PNPLA3 genotype or diet. In addition, there were a correlation between plasma CE 16:1/16:0 and liver PNPLA3 mRNA after a single dose of PNPLA3 ASO (FIG. 2). The ratio between cholesteryl palmitoleate and cholesteryl palmitate (CE 16:1/16:0) in human plasma or serum can be measured by mass spectrometric detection after separation using either liquid or gas chromatography.