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Evaluation of Antisense Oligonucleotides Therapy Targeting Hsd17b13 in a Fibrosis Mice Model.
Journal of Lipid Research 2024 Februrary 2
OBJECTIVE: Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for non-alcoholic steatohepatitis (NASH).. The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model.
METHODS: Hsd17b13 ASO was tested in primary mouse hepatocytes for efficacy and specificity. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 4 weeks for disease induction and then administered with a scramble oligonucleotide negative control or Hsd17b13 ASO for 8 weeks. At the time of sacrifice, hepatic histology, gene expression, and serum panels were examined.
RESULTS: In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knock-down of the Hsd17b13 gene. In CDAHFD induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased expression of fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. While Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis.
CONCLUSION: Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.
METHODS: Hsd17b13 ASO was tested in primary mouse hepatocytes for efficacy and specificity. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 4 weeks for disease induction and then administered with a scramble oligonucleotide negative control or Hsd17b13 ASO for 8 weeks. At the time of sacrifice, hepatic histology, gene expression, and serum panels were examined.
RESULTS: In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knock-down of the Hsd17b13 gene. In CDAHFD induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased expression of fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. While Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis.
CONCLUSION: Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.
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