Inhibition of hsd17b13 in the treatment of liver disease in patients expressing the pnpla3 i148m variation
Patent Information
- Application Number
- HK42026125209
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2017-10-11
- Filing Date
- 2026-06-23
- Publication Date
- 2026-09-18
- Estimated Expiration
- 2038-10-10
Smart Images
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Abstract
Description
Abstract This invention relates to a hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) inhibitor for reducing or inhibiting HSD17B13 gene expression or HSD17B13 protein function during treatment for treating non-alcoholic or alcoholic liver disease in human subjects with patatin-like phospholipase domain 3 (PNPLA3) protein containing the I148M variant, wherein the alcoholic liver disease includes one or more of cirrhosis, steatosis, or hepatocellular carcinoma caused by alcohol consumption; and the non-alcoholic liver disease includes one or more of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis not caused by alcohol consumption, steatosis not caused by alcohol consumption, or hepatocellular carcinoma not caused by alcohol consumption.
Claims
1. An inhibitor of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) for use in reducing or inhibiting HSD17B13 gene expression or the function of HSD17B13 protein in the treatment of a non-alcoholic or alcoholic liver disease in a human subject having a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an 1148M variation, wherein the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption; and wherein the non-alcoholic liver disease comprises one or more of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis not caused by alcohol consumption, steatosis not caused by alcohol consumption, or hepatocellular carcinoma not caused by alcohol consumption.
2. The inhibitor for the use according to claim 1, wherein the human subject has been identified as being a candidate for treating a non-alcoholic or alcoholic liver disease by inhibiting HSD17B13 by using the method as defined in any one of claims 4 to 10.
3. The inhibitor for use according to claim 1 or claim 2, wherein the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I148M variation.
4. A method for identifying a human subject as a candidate for reducing or inhibiting hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene expression or the function of HSD17B13 protein in the treatment of a non-alcoholic or alcoholic liver disease, the method comprising: determining whether or not a sample from the subject comprises a nucleic acid molecule encoding a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation, and / or a PNPLA3 protein comprising an 1148M variation; and identifying the subject as a candidate for reducing or inhibiting HSD17B13 gene expression or the function of HSD17B13 protein in the treatment of a non-alcoholic or alcoholic liver disease when the nucleic acid molecule encoding the PNPLA3 protein comprising the I148M variation, and / or the PNPLA3 protein comprising the 1148M variation is detected, wherein the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption; and wherein the non-alcoholic liver disease comprises one or more of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis not caused by alcohol consumption, steatosis not caused by alcohol consumption, or hepatocellular carcinoma not caused by alcohol consumption.
5. The method according to claim 4 wherein the nucleic acid molecule encoding the PNPLA3 protein comprising the I148M variation comprises genomic DNA, mRNA, or a cDNA obtained from mRNA.
6. The method according to claim 5, wherein: the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31; the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34; the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35; the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; or the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.
7. The method according to claim 5 or claim 6, wherein: the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I148M variation; the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:34 and encoding a PNPLA3 protein which comprises the I148M variation; the mRNA comprises the nucleotide sequence according to SEQ ID NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I148M variation; the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I148M variation; or the cDNA comprises the nucleotide sequence according to SEQ ID NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.
8. The method according to any one of claims 4 to 7, wherein detecting the nucleic acid molecule encoding the PNPLA3 protein comprising the I148M variation comprises: sequencing at least a portion of the nucleic acid molecule, wherein the portion comprises the codon which encodes the I148M variation; or hybridizing the first nucleic acid with a probe or primer that specifically hybridizes to a portion of the nucleic acid molecule, wherein the portion comprises the codon encoding the I148M variation.
9. The method according to claim 8, wherein the probe or primer is an allele-specific probe or primer, and wherein the probe or primer optionally comprises a label.