title: Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.
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 thein vivoexpansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation ofFAHknock-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 intoFAH-/-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.
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Quanjun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Yang
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Qingjian
authors.initials: Q
authors.lastname: Zou
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Chengdan
authors.initials: C
authors.lastname: Lai
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.|Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Research Center for Liver Fibrosis, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital and.|Biomedical Research Center, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences.|National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, and.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council (MRC) Building, Cambridge CB2 0XY, United Kingdom.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Shuhan
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong SAR, China.
authors.forename: Tak-Shing
authors.initials: TS
authors.lastname: Siu
authors.affiliation: Department of Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong SAR, China.
authors.forename: Sidney
authors.initials: S
authors.lastname: Tam
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.|Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China.|Department of Medicine, University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong, China, and.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of Metabolism and Cell Fate, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, Guangdong, China.
authors.forename: Baoming
authors.initials: B
authors.lastname: Qin
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Xichen
authors.initials: X
authors.lastname: Bao
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China, miguel@gibh.ac.cn.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.|Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
authors.affiliation: From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China, lai_liangxue@gibh.ac.cn.|CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Liangxue
authors.initials: L
authors.lastname: Lai
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D011817:Rabbits; D020176:Tyrosinemias / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D006867:Hydrolases; C020156:fumarylacetoacetase
keywords: animal model; gene knock-out; liver; stem cells; transplantation