文献类型：期刊文献

英文题名：Prevention of Portal-Tract Fibrosis in Zfyve19-/- Mouse Model with Adeno-Associated Virus Vector Delivering ZFYVE19

作者：Zhang, Yanan[1,2];Tang, Dingyue[3];Wang, Li[2];Yang, Jing[1,2];Wu, Xia[4];Xiao, Xiao[3];Wang, Jian-She[2,5]

机构：[1]Fudan Univ, Jinshan Hosp, Dept Pediat, Shanghai, Peoples R China;[2]Fudan Univ, Childrens Hosp, Ctr Pediat Liver Dis, Shanghai 201102, Peoples R China;[3]East China Univ Sci & Technol, Sch Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[5]Shanghai Key Lab Birth Defect, Shanghai, Peoples R China

年份：2023

卷号：34

期号：23-24

起止页码：1219

外文期刊名：HUMAN GENE THERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001111038300001)】；

基金：The work was supported by the National Key Research and Development Program of China (Grant No. 2021YFC2700800) and the Shanghai Municipal Science and Technology Major Project (19140901600).

语种：英文

外文关键词：AAV; gene therapy; mouse model; portal-tract fibrosis; ZFYVE19

摘要：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 x 10(11) vg/kg), whereas AAV-hZFYVE19 at a higher dose gradually lost the abovementioned benefits and even caused deterioration at the highest dose of 5 x 10(12) vg/kg. These observations verified the pathogenicity of ZFYVE19 deficiency and suggested that the ZFYVE19 gene needs to function well at an optimal level of expression; both too low and too high a ZFYVE19 expression may be harmful.