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 nonalcoholic 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. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (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 fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. 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.

中文翻译：

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在纤维化小鼠模型中针对 Hsd17b13 的反义寡核苷酸疗法的评估

人类遗传证据表明 17-β 羟基类固醇脱氢酶 13 (HSD17B13) 功能丧失变异对肝纤维化疾病具有保护作用。尽管纤维化模型中 Hsd17b13 反义寡核苷酸 (ASO) 或 siRNA 的临床前实验数据有限，但几种 ASO 和 siRNA 方法正在临床测试作为非酒精性脂肪性肝炎 (NASH) 的潜在疗法。本研究的目的是评估 Hsd17b13 ASO 在临床前晚期 NASH 样肝纤维化体内模型中的治疗潜力。原代肝细胞的体外测试表明，Hsd17b13 ASO 对 Hsd17b13 基因的敲低表现出强大的功效和特异性。在胆碱缺乏、L-氨基酸定义的 HFD (CDAHFD) 诱导的脂肪变性和纤维化小鼠中，治疗性给予 Hsd17b13 ASO 导致肝脏 Hsd17b13 基因表达显着且呈剂量依赖性减少。 CDAHFD组表现出显着升高的肝酶水平、肝脂肪变性评分、肝纤维化以及纤维化和炎症基因表达增加，表明晚期NASH样肝纤维化表型。虽然Hsd17b13 ASO治疗显着影响肝脂肪变性，但对肝纤维化没有影响。我们的研究结果首次证明，Hsd17b13 ASO 在体外和体内均有效抑制 Hsd17b13 基因表达，并对小鼠肝脏脂肪变性具有调节作用，但不影响 NASH CDAHFD 小鼠模型的纤维化。