Prevention of Portal-Tract Fibrosis in Zfyve19 −/− Mouse Model with Adeno-Associated Virus Vector Delivering ZFYVE19

作者：Yanan Zhang, Yanan Zhang, Li Wang, Jing Yang, Li Wang, Jing Yang, Xia Wu, Xiao Xiao, Jian‐She Wang · 发表于：Human Gene Therapy · 年份：2023 · DOI：10.1089/hum.2023.041 · 被引用次数：5 · 研究领域：RNA regulation and disease、Genetics and Neurodevelopmental Disorders、RNA Interference and Gene Delivery

Zinc finger FYVE-type containing 19 (ZFYVE19) deficiency, caused by biallelic ZFYVE19 complete loss-of-function variants, is a recently identified chronic hepatobiliary disorder characterized by obvious portal-tract fibrosis, increased numbers of bile ducts with malformations, and abnormal levels of serum markers of hepatobiliary injury. As liver-targeted adeno-associated virus (AAV) gene therapy has been used successfully in hepatobiliary diseases, liver-targeted gene therapy has been explored in a mouse model of this disorder. Three ZFYVE19 AAV vectors (AAV-hZFYVE19, AAV-hZFYVE19-m, and AAV-hZFYVE19-co) were constructed and injected into Zfyve19−/− mice, which were treated with alpha-naphthyl isothiocyanate, a hepatobiliary toxin. Hematoxylin/eosin, immunohistochemical staining, immunofluorescence staining, Sirius Red staining, real-time quantitative PCR, and Western blotting of liver tissue, along with serum hepatobiliary injury marker analyses, were performed to evaluate the effects of gene therapy. AAV-hZFYVE19 decreased serum hepatobiliary injury markers, portal-tract inflammation, ductal hyperplasia, and portal-tract fibrosis in the Zfyve19−/− model mice most substantially at a relatively low dose (1 × 1011 vg/kg), whereas AAV-hZFYVE19 at a higher dose gradually lost the abovementioned benefits and even caused deterioration at the highest dose of 5 × 1012 vg/kg. These observations verified the pathogenicity of ZFYVE19 deficiency and suggested that the ZFYVE19 gene need...