Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1

作者：Li Li, Quanjun Zhang, Huaqiang Yang, Qingjian Zou, Chengdan Lai, Fei Jiang, Ping Zhao, Zhiwei Luo, Jiayin Yang, Qian Chen, Yan Wang, Philip N. Newsome, Jon Frampton, Patrick H. Maxwell, Wenjuan Li, Shuhan Chen, Dongye Wang, Tak-Shing Siu, S Tam, Hung‐Fat Tse, Baoming Qin, Xichen Bao, Miguel A. Esteban, Liangxue Lai · 发表于：Journal of Biological Chemistry · 年份：2017 · DOI：10.1074/jbc.m116.764787 · 被引用次数：19 · 研究领域：CRISPR and Genetic Engineering、Metabolism and Genetic Disorders、Virus-based gene therapy research

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH −/− rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantat...