WO2021211959A2 - Procédés et compositions pour le traitement de la stéatohépatite induite par un médicament - Google Patents

Procédés et compositions pour le traitement de la stéatohépatite induite par un médicament Download PDF

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WO2021211959A2
WO2021211959A2 PCT/US2021/027670 US2021027670W WO2021211959A2 WO 2021211959 A2 WO2021211959 A2 WO 2021211959A2 US 2021027670 W US2021027670 W US 2021027670W WO 2021211959 A2 WO2021211959 A2 WO 2021211959A2
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subject
hsd17b13
inhibitor
drug
cancer
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PCT/US2021/027670
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WO2021211959A3 (fr
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Heather Kay Webb HSU
Kris KOWDLEY
Michael Carleton
William Michael Gallatin
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Inipharm, Inc.
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Publication of WO2021211959A2 publication Critical patent/WO2021211959A2/fr
Publication of WO2021211959A3 publication Critical patent/WO2021211959A3/fr

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  • DILI Drug induced liver injury
  • Non-alcoholic fatty liver disease is recognized as a leading cause of liver disease in the western world and has increased in frequency over recent decades.
  • the prevalence of NAFLD ranges from 20 to 30% in the general population, depending on diagnostic criteria and the specific definition applied, with rates exceeding 50% in diabetic and obese patients.
  • NAFLD includes a spectrum of liver diseases ranging from simple hepatic steatosis to non alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC).
  • Drug induced steatosis (DIS) or steatohepatitis (DISH) is a rare form of DILI with fewer than 2% of all cases of NASH attributed to drugs.
  • Drugs capable of inducing steatosis and steatohepatitis can be divided into three groups: drugs that induce metabolic changes and can precipitate latent NASH (e.g., tamoxifen), drugs that cause steatosis and steatohepatitis independently (e.g., amiodarone, perhexiline maleate), and drugs that induce sporadic events of steatosis/steatohepatitis (e.g., carbamazepine).
  • drugs that induce metabolic changes and can precipitate latent NASH e.g., tamoxifen
  • drugs that cause steatosis and steatohepatitis independently e.g., amiodarone, perhexiline maleate
  • drugs that induce sporadic events of steatosis/steatohepatitis e.g., carbamazepine
  • DILI drug induced liver injury
  • the method comprising administering to a subject in need thereof a HSD17B13 inhibitor.
  • the subject in need thereof is undergoing or has undergone treatment with a therapy that cause liver injuries such as steatohepatitis.
  • a method of treating, preventing, or delaying drug induced liver injury (DILI) in a subject in need thereof comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the drug induced liver injury is caused by a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the drug induced liver injury is caused by a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the drug induced liver injury is caused by a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the drug induced liver injury is caused by a nonsteroidal anti-inflammatory drugs (NSAID).
  • the NSAID is pirprofen.
  • the drug induced liver injury is drug induced steatosis (DIS).
  • the drug induced liver injury is drug induced steatohepatitis (DISH).
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the drug are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the drug has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject.
  • TG liver triglyceride content
  • the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory-Denk Bodies
  • the drug induced steatohepatitis is caused by a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the drug induced steatohepatitis is caused by a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the drug induced steatohepatitis is caused by a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the drug induced steatohepatitis is caused by a nonsteroidal anti inflammatory drugs (NSAID).
  • NSAID nonsteroidal anti inflammatory drugs
  • theNSAID is pirprofen.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the drug are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the drug has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject.
  • TG liver triglyceride content
  • the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory-Denk Bodies
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the cancer drug are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the cancer drug are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the cancer drug has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject.
  • TG liver triglyceride content
  • the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory-Denk Bodies
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the cardiovascular drug is amiodarone.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the drug are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the drug has been discontinued.
  • tamoxifen is administered to treat breast cancer.
  • tamoxifen is administered to prevent contralateral breast cancer.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and tamoxifen are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and tamoxifen are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once tamoxifen has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject.
  • TG liver triglyceride content
  • the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory-Denk Bodies
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is lung cancer.
  • the cancer is head and neck cancer.
  • the cancer is colon cancer.
  • the cancer has been treated with tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer has been treated with tamoxifen. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the cancer treatment are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the cancer treatment are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the cancer treatment has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject.
  • TG liver triglyceride content
  • ATL plasma alanine aminotransferase
  • AST plasma aspartate aminotransferase
  • the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • Adrp plasma adipose differentiation-related protein
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol - 3-phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPARa), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory - Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory - Denk Bodies
  • the SERM is tamoxifen or toremifene.
  • the SERM is tamoxifen.
  • the SERM is administered to treat breast cancer.
  • the SERM is administered to prevent contralateral breast cancer.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the SERM are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the SERM has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol - 3-phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory - Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory - Denk Bodies
  • the antifolate is methotrexate.
  • the antifolate is administered to treat cancer.
  • the antifolate is administered to treat rheumatoid arthritis.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound.
  • the HSD17B13 inhibitor is an RNAi.
  • the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously.
  • the HSD17B13 inhibitor and the SERM are administered to the subject sequentially.
  • the HSD17B13 inhibitor is administered once the SERM has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject.
  • TG liver triglyceride content
  • the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • MDBs Mallory-Denk Bodies
  • a method of preventing a decrease in hepatocyte triglyceride secretion in a subject that has been administered or is being administered an additional therapeutic agent comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the additional therapeutic agent is a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the additional therapeutic agent is a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the additional therapeutic agent is a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the additional therapeutic agent is a nonsteroidal anti-inflammatory drugs (NSAID).
  • the NSAID is pirprofen.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the additional therapeutic agent has been discontinued.
  • the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject.
  • the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.
  • the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.
  • the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).
  • the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.
  • the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad).
  • the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.
  • the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • HSD17B13 inhibitors can be used to expand the usefulness of drugs by protecting patients from liver damage resulting from targeted therapy, such as chemotherapy induced hepatic steatosis and progression to steatohepatitis.
  • Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • a number refers to that number plus or minus 10% of that number.
  • the term ‘about’ a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • HSD17B13 means hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13.
  • HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13 (including genomic DNA comprising introns and exons).
  • HSD17B13 can also refer to any amino acid sequence of HSD17B13 (may include secondary or tertiary structures of the protein molecule), encoded by a DNA sequence and/or RNA sequence. The target may be referred to in either upper or lower case.
  • fragment or “derivative” when referring to a protein (e.g., HSD17B13) generally means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s).
  • the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins.
  • modulate generally means to interact with a target protein (e.g., HSD17B13) either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.
  • a target protein e.g., HSD17B13
  • a modulator generally refers to a compound that alters an activity of a target.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor (e.g., HSD17B13 inhibitor), which decreases the magnitude of one or more activities of a target (e.g., a HSD17B13 protein).
  • an inhibitor completely prevents one or more activities of a target.
  • a modulator changes the cellular distribution of the target (e.g., a HSD17B13 protein).
  • target activity generally refers to a biological activity capable of being modulated by a modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, and amelioration of one or more symptoms associated with a liver disease or condition.
  • the term “subject,” “patient,” or “individual” generally encompasses mammals, non mammals, and a biological entity containing expressed genetic materials.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • the subject may be diagnosed or suspected of being at high risk for a liver condition or disease. In some cases, the subject may be diagnosed or suspected of being at risk for a condition or disease that needs to receive a particular therapy, which could cause or exacerbate a liver condition or disease. In some cases, the subject is not necessarily diagnosed or suspected of being at risk for the liver disease or condition.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, prevention of sequelae, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • pharmaceutically acceptable generally refers a material, such as a carrier, diluent, or formulation, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutical composition” generally refers to a mixture of a compound (e.g., a HSD17B13 inhibitor), described herein with other chemical components, such as carriers, stabilizers, diluents, surfactants, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, subcutaneous, intramuscular, pulmonary and topical administration.
  • an “effective amount” or “therapeutically effective amount,” as used herein, generally refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition, required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • compositions described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, disorder or condition, such as a liver disease or condition to prevent the subject from developing the liver disease or condition.
  • a particular disease, disorder or condition such as a liver disease or condition to prevent the subject from developing the liver disease or condition.
  • Such an amount is defined to be a “prophylactically effective amount or dose.”
  • the precise amounts also depend on the subject's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.
  • carrier generally refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • dilute refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
  • the drug induced liver injury is drug induced steatosis (DIS).
  • the drug induced liver injury is drug induced steatohepatitis (DISH).
  • the drug induced liver injury is hepatic sinusoidal Injury.
  • the drug induced liver injury is liver carcinoma.
  • cytotoxic chemotherapies targeting various forms of cancer ameliorate symptoms and prolong survival of patients suffering from cancer or other diseases.
  • those pharmacological compounds come with a price because they exhibit many adverse side effects.
  • the adverse side effects generally may include hepatic injuries.
  • many patients receiving chemotherapy develop lipid metabolism disorders.
  • the administration of chemotherapy to patients with lipid metabolism disorders may increase the risk of liver damage.
  • Chemotherapy induces various histological changes of the liver parenchyma including steatosis, chemotherapy-associated steatohepatitis (CASH), or sinusoidal injury sinusoidal obstruction syndrome (SOS).
  • CASH chemotherapy-associated steatohepatitis
  • SOS sinusoidal injury sinusoidal obstruction syndrome
  • the mechanism of chemotherapy -induced hepatic injury may be secondary to production of reactive oxygen species (ROS), intended to induce tumor cell apoptosis.
  • ROS reactive oxygen species
  • Previously steatotic livers were thought to be most susceptible to chemotherapy-induced injury due to impaired regenerative capability and abnormal innate immunity.
  • Chemotherapies and other pharmacological compounds which induce hepatic steatosis and can cause more severe liver injury are often not discontinued to address increased risk of liver injury since the disease being treated, such as breast or lung cancer, can be lethal.
  • the drug induced liver injury is caused by a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the drug induced liver injury is caused by a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the drug induced liver injury is caused by a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the drug induced liver injury is caused by a nonsteroidal anti inflammatory drugs (NSAID).
  • theNSAID is pirprofen.
  • DILI drug induced liver injury
  • the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the drug induced liver injury is caused by a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the drug induced liver injury is caused by a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the drug induced liver injury is caused by a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the drug induced liver injury is caused by a nonsteroidal anti-inflammatory drugs (NSAID).
  • theNSAID is pirprofen.
  • the drug induced liver injury is drug induced steatosis (DIS).
  • the drug induced liver injury is drug induced steatohepatitis (DISH).
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the drug induced steatohepatitis is caused by a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the drug induced steatohepatitis is caused by a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the drug induced steatohepatitis is caused by a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the drug induced steatohepatitis is caused by a nonsteroidal anti-inflammatory drugs (NSAID).
  • the NSAID is pirprofen.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a cancer drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a cardiovascular drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the cardiovascular drug is amiodarone.
  • DISH drug induced steatohepatitis
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • NSAID nonsteroidal anti-inflammatory drugs
  • the NSAID is pirprofen or ibuprofen.
  • the NSAID is pirprofen.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a tamoxifen in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • tamoxifen is administered to treat breast cancer.
  • tamoxifen is administered to prevent contralateral breast cancer.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) in a subject that has undergone treatment for a cancer comprising breast cancer, ovarian cancer, non small cell lung cancer, lung cancer, head cancer, neck cancer, and colon cancer, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer has been treated with tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer has been treated with tamoxifen.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a selective estrogen receptor modulator (SERM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the SERM is tamoxifen or toremifene.
  • the SERM is tamoxifen.
  • the SERM is administered to treat breast cancer.
  • the SERM is administered to prevent contralateral breast cancer.
  • Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by an antifolate in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the antifolate is methotrexate.
  • the antifolate is administered to treat cancer.
  • the antifolate is administered to treat rheumatoid arthritis.
  • a method of preventing a decrease in hepatocyte triglyceride secretion in a subject that has been administered or is being administered an additional therapeutic agent comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.
  • the additional therapeutic agent is a cancer drug.
  • the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.
  • the cancer drug is tamoxifen.
  • the additional therapeutic agent is a cardiovascular drug.
  • the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.
  • the additional therapeutic agent is a psychiatric drug.
  • the psychiatric drug is amitriptyline, clozapine, or any combination thereof.
  • the additional therapeutic agent is a nonsteroidal anti-inflammatory drugs (NSAID).
  • the NSAID is pirprofen.
  • Steatosis is a type of fatty liver disease characterized by fat accumulation in liver without inflammation .
  • the effect of mild to moderate steatosis without associated inflammation on postoperative outcome is likely to be small.
  • steatosis is associated with infection-related complications but not with major complications or postoperative mortality.
  • patients with steatosis had increased blood loss, more postoperative complications, and a longer mean intensive-care-unit stay per patient as compared with matched control patients with healthy livers.
  • Fluorouracil (5-FU) which remains the backbone of modern chemotherapy, has been linked to the development of steatosis. Reports indicate the development of steatosis in 30 to 47% of patients after 5-FU therapy, although some changes may be reversible.
  • Steatohepatitis is a type of fatty liver disease characterized by inflammation of the liver with concurrent fat accumulation in liver. Irinotecan is clearly associated with steatohepatitis, with a rate of 20.2% seen in patients administered this drug, compared with 4.4% in those not having chemotherapy. This effect is exacerbated by baseline obesity.
  • One study shows that steatohepatitis is found in 24.6% in those with a BMI of 25 kg/m 2 or more who were administered irinotecan, but only 12.1% in irinotecan treated patients with a BMI less than 25 kg/m 2 . Steatohepatitis increases the risk of liver failure and postoperative complications following major hepatectomy.
  • Sinusoidal injury ranges from sinusoidal dilation to hepatic sinusoidal obstruction syndrome, also termed venoocclusive disease, which can progress to regenerative nodular hyperplasia.
  • venoocclusive disease also termed venoocclusive disease, which can progress to regenerative nodular hyperplasia.
  • Oxidative stress to the sinusoidal endothelial cells lining the sinusoids the initial event, leads to subintimal thickening and extravasation of erythrocytes into the subendothelial space of Disse (perisinusoidal space).
  • Sinusoidal endothelial cells and erythrocytes embolize in sinusoids and block venous outflow, resulting in hepatic congestion and sinusoidal dilatation.
  • a fibrotic reaction in the sinusoids can lead to obliteration of central venules, leading to hepatic sinusoidal obstruction syndrome.
  • Rates of injury are universally higher in patients receiving oxaliplatin-based chemotherapy. Studies show that oxaliplatin is associated with a 10-fold increase in sinusoidal dilation compared with no chemotherapy (18.9% versus 1.9%). In one study involving administration of chemotherapy, high-grade injuries were much more prominent in the group administered chemotherapy (41%) compared to the control group (0%). Oxaliplatin and other platinum compounds lead to the generation of ROS and could result in depletion of glutathione from sinusoidal endothelial cells (SECs).
  • SECs sinusoidal endothelial cells
  • Cisplatin has been shown to cause actin dissociation, which can upregulate matrix-metalloproteinases-9 (MMP-9) activity. Morbidity following hepatectomy is significantly higher in patients with evidence of sinusoidal obstruction syndrome, although there is no increase in mortality. Sinusoidal injury also significantly increases hospital stay. Oxaliplatin is associated with an increased transfusion requirement compared to patients receiving 5 FU/leucovorin or no chemotherapy. It has been suggested that increased blood loss is directly attributable to these vascular lesions.
  • MMP-9 matrix-metalloproteinases-9
  • the subject being treated for drug induced liver injury has been diagnosed with an additional pathology.
  • the subject has been diagnosed with alcoholic liver disease (ALD).
  • the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • NAFLD is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
  • the subject has been diagnosed with insulin resistance, obesity, and/or other metabolic syndromes.
  • the subject has been diagnosed with hepatitis.
  • the subject has been diagnosed with hepatic cirrhosis.
  • the drug induced liver injury for example steatohepatitis, exacerbates a pre-existing liver disease.
  • the pre-existing liver disease is alcoholic liver disease (ALD).
  • the pre-existing liver disease is non alcoholic fatty liver disease (NAFLD).
  • the pre-existing liver disease is non-alcoholic fatty liver (NAFL).
  • the pre-existing liver disease is non alcoholic steatohepatitis (NASH).
  • the pre-existing liver disease is insulin resistance, obesity, and/or other metabolic syndromes.
  • the pre-existing liver disease is hepatitis.
  • the pre-existing liver disease is hepatic cirrhosis.
  • ALD Alcoholic Liver Disease
  • ALD also called alcohol -related liver disease (ARLD)
  • ARLD alcohol -related liver disease
  • NAFLD Non-alcoholic Fatty Liver Disease
  • Non-alcoholic fatty liver disease comprises a spectrum of phenotypes ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Obesity, insulin resistance, and the resulting metabolic syndrome has led to an increased prevalence of non-alcoholic fatty liver disease. This has been estimated to be present in more than 20% of patients planned for hepatectomy. Steatotic liver is more vulnerable to injury from general anesthesia and ischemia/reperfusion. Protective mechanisms against oxidative stress are significantly impaired in steatosis, and impaired energy homeostasis further sensitizes steatotic livers to surgical stress. Regeneration is delayed in steatotic livers, with a resulting prolongation of liver dysfunction.
  • NASH Non-alcoholic steatohepatitis
  • NASH is a clinical and histological subset of NAFLD that is associated with increased all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular mortality, and increased incidence of both liver-related and non-liver-related cancers.
  • NASH is diagnosed clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning of liver hepatocytes, often with varying degrees of fibrosis.
  • NASH progresses with increasing degrees of fibrosis, with cirrhosis developing in a subset of patients, with the most common complication of cirrhosis being hepatocellular carcinoma.
  • Metabolic perturbations including insulin resistance, impaired glycemic control, and altered lipid metabolism, have been hypothesized to contribute to the molecular pathogenesis of NAFLD and NASH.
  • Hepatic cirrhosis is a disease in which healthy liver tissue is replaced with scar tissue.
  • the scar tissue blocks the blood flow through the liver and slows the liver’s ability to process nutrients, hormones, drugs, and natural toxins. It usually takes months or even years for the scar tissue to build and eventually develop cirrhosis.
  • NAFLD, ALD, or viral infections of the liver all can cause cirrhosis.
  • anything, such as certain diseases or conditions, that damages the liver can cause cirrhosis, including cystic fibrosis, glycogen storage diseases, alpha- 1 antitrypsin deficiency, or autoimmune diseases of the liver.
  • Hepatitis is inflammation of the liver tissue. Some people with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.
  • Hepatitis is most commonly caused by the viruses hepatitis A, B, C, D, and E. Other causes include heavy alcohol use, certain medications, toxins, other infections, autoimmune diseases, and non-alcoholic steatohepatitis (NASH). Hepatitis A and E are mainly spread by contaminated food and water. Hepatitis B is mainly sexually transmitted, but may also be passed from mother to baby during pregnancy or childbirth and spread through infected blood. Hepatitis C is commonly spread through infected blood such as may occur during needle sharing by intravenous drug users. Hepatitis D can only infect people already infected with hepatitis B.
  • NASH non-alcoholic steatohepatitis
  • HSD17Bs 17P-Hydroxysteroid dehydrogenases
  • HSD17Bs are a group of enzymes catalyzing the conversion between 17-keto- and 17-hydroxysteroids.
  • Most members of this family participate in the regulation of biological activity of sex hormones, including HSD17B1, HSD17B2, HSD17B3, HSD17B5 and HSD17B6.
  • Other members are also involved in fatty acid metabolism, cholesterol biosynthesis, and bile acid production in vivo.
  • HSD17B13 is identified as a new lipid droplet (LD)-associated protein and its expression is mainly restricted to the liver.
  • LD lipid droplet
  • HSD17B13 is among one of the most abundantly expressed hepatic LD-associated proteins Further, HSD17B13 is shown to locate on the surface of liver lipid droplets and its expression is markedly upregulated in the livers of patients and mice with NAFLD. A tissue distribution study demonstrated that HSD17B13 is also highly abundant in mouse liver, with very low levels in ovary, kidney, brain, lung, skeletal muscle, testis, further suggesting its key role in liver physiology.
  • Human HSD17B13 gene is located at chromosome 4q22.1 and its protein sequence shares a high degree of homology (78%) with HSD17B11, which is also mapped to the same chromosome. Similar to other 17BHSD members, HSD17B13 contains two conserved motifs, with one TGXGXXXG motif related to NAD(P)(H) binding and one YXXXK motif important for its catalytic activity.
  • HSD17B13 expression is related to metabolic nuclear receptors (NRs).
  • NRs metabolic nuclear receptors
  • NRs metabolic nuclear receptors
  • LXRs liver X receptors
  • FXR FXR
  • PPARs PPARs
  • transcription factors such as sterol regulatory-element binding proteins (SREBPs).
  • LXRs including LXRa (NR1H3) and LXRP (NR1H2), are members of the NR superfamily and are key regulators in both cholesterol and fatty acid metabolism.
  • LXRs can be activated by naturally produced oxysterols and synthetic compounds such as T0901317 and GW3965. T0901317 induces hepatic steatosis via activating LXRs.
  • LXRa and SREBP-lc have been described as major contributors in NAFLD.
  • Gene profiling analysis revealed that LXR activation may induce expression of several members of the HSD17B family, including HSD17B2, HSD17B5, and HSD17Bll.
  • the LXR agonist T0901317 significantly induces HSD17B13 expression at both mRNA and protein levels in mouse liver.
  • the induction of HSD17B13 expression by T0901317 was abolished in LXRa-/- mice but not in LXRp-/- mice, suggesting LXRa plays an important role in HSD17B13 gene transcription.
  • LXRa-induced HSD17B13 expression is markedly attenuated in SREBP-lc knock out mice indicating that LXRa upregulates HSD17B13 expression in an SREBP-lc-dependent manner.
  • Bioinformatical analysis further reveals a putative SREBP-1 response element (SRE) in the promoter region of HSD17B13 gene, which was confirmed to be functional by a luciferase reporter assay.
  • SRE SRE-1 response element
  • NRF2 NF-E2 p45 -related factor 2
  • NRF2 the master regulator of cellular redox homeostasis, when activated can ameliorate steatosis, inflammation and fibrosis in experimental models of steatohepatitis.
  • the NRF2 agonist TBE-31 has been shown to ameliorate NASH in a mouse model.
  • HSD17B13 catalyzes the oxidation of estradiol and retinol.
  • Estradiol is an agonist of estrogen receptors (ER, ERR).
  • the oxidized product of retinol, retinoic acid is an agonist for the retinoic acid receptor (RAR) and retinoid X receptor (RXR).
  • RAR retinoic acid receptor
  • RXR retinoid X receptor
  • Nuclear receptors ER, ERR, RAR and RXR negatively regulate cellular antioxidant responses through inhibition of NRF2, the master regulator of cellular redox homeostasis.
  • Complex formation between nuclear receptors and NRF2 block binding of NRF2 to antioxidant response element (ARE) enhancers preventing NRF2 transactivation of a battery of genes involved in antioxidant responses. Decreased cellular retinoic acid pools induced by HSD17B13 inhibition may likely lead to NRF2 activation, decreasing fibrosis stimulated by retinoic acid-stimulated stellate cells.
  • ARE antioxidant response element
  • HSD17B13 inhibitors may compete with HSD17B13 inhibitors in interacting with HSD17B13 in many signaling pathways described herein.
  • HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than a retinol’s affinity to said HSD17B13 protein.
  • a HSD17B13 protein may comprise enzymatic activity, which may comprise retinol dehydrogenase activity.
  • HSD17B13 inhibitors are configured to decrease HSD17B13’s enzymatic activity by at least 2%, 4%, 6%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.
  • HSD17B13 inhibitors are configured to decrease HSD17B13’s enzymatic activity by at most 99%, 98%, 96%, 94%, 92%, 90%, 88%, 86%, 84%, 82%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 8%, or 6%.
  • HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as retinol.
  • HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than a fatty acid’s affinity to said HSD17B13 protein.
  • HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as fatty acid. In some embodiments, HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than an estradiol’s affinity to said HSD17B13 protein. In some embodiments, HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as estradiol.
  • HSD17B13 could also have potential as a biomarker of advanced liver disease, such NASH and liver cancer.
  • HSD17B13 inhibitors comprise a nucleic acid molecule that is configured to cause genetic perturbation of HSD17B13 gene resulting in reduced RNA and/or protein expression of HSD17B13.
  • the nucleic acid molecule may comprise genomic DNA, mRNA, or cDNA.
  • the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor
  • the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor is ARO-HSD.
  • the LC-MS/MS based Estradiol (E2) turnover assay monitors the production of estrone (El) by the action of HSD17B13 in the presence of the co-factor NAD+.
  • the assays were performed in 96-well plates (Eppendorf deep well Plate 96/500) in an 80 m ⁇ reaction volume containing the following reagents (final concentrations): 4 mM Estradiol (Cayman; #10006315); 6 mMNAD + (Sigma; #N0623); 30 nM HSD17B13 enzyme (in-house E. coli expressed His- tagged, purified, soluble protein); 1 M potassium phosphate buffer pH 7.4, and 0.5% DMSO. Reactions proceeded for 2 hours at 26.5°C. Estradiol conversion to Estrone was quantitated by LC-MS/MS based analyte detection, using LCMS grade reagents, as follows:
  • Enzyme activity in the presence of inhibitor compounds was expressed as a percentage of the uninhibited enzyme activity, and plotted versus inhibitor concentration (ten concentrations, ranging from 30 mM - 1.5 nM).
  • IC50 values were calculated using non-linear regression and a four-parameter logistic model on GraphPad Prism software (GraphPad Software, La Jolla, CA). IC50 values were converted into Ki values using the equation:
  • Ki IC50/([S]/Km + 1) where [S] is the substrate concentration and Km is the Michaelis constant for the substrate.

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Abstract

L'invention concerne des procédés associés au traitement d'une lésion hépatique induite par un médicament de traitement (DILI) et plus spécifiquement un médicament induisant la stéatohépatite (DISH) ; le procédé comprenant l'administration d'un inhibiteur de la 17-bêta-hydroxystéroïde déshydrogénase 13 (HSD17B13).
PCT/US2021/027670 2020-04-18 2021-04-16 Procédés et compositions pour le traitement de la stéatohépatite induite par un médicament WO2021211959A2 (fr)

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