1. Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1
- Author
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Patrick H. Maxwell, Huaqiang Yang, Qingjian Zou, Xichen Bao, Quanjun Zhang, Jiayin Yang, Wenjuan Li, Zhiwei Luo, Fei Jiang, Miguel A. Esteban, Jonathan Frampton, Liangxue Lai, Sidney Tam, Chengdan Lai, Philip N. Newsome, Tak-Shing Siu, Dongye Wang, Shuhan Chen, Qian Chen, Ping Zhao, Baoming Qin, Hung-Fat Tse, Yan Wang, Li Li, Maxwell, Patrick [0000-0002-0338-2679], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Hydrolases ,Genetic enhancement ,gene knock-out ,Biology ,Kidney ,liver ,Biochemistry ,Tyrosinemia ,03 medical and health sciences ,Gene Knockout Techniques ,stem cells ,Internal medicine ,medicine ,Animals ,Humans ,Tyrosine ,Molecular Biology ,Gene knockout ,Tyrosinemias ,animal model ,Molecular Bases of Disease ,Cell Biology ,medicine.disease ,3. Good health ,Transplantation ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Hepatocytes ,Fumarylacetoacetate hydrolase ,Female ,Rabbits ,Stem cell ,Liver Failure ,transplantation - Abstract
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 transplantation of wild-type rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1.
- Published
- 2016