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dc.contributor.authorLi, Li
dc.contributor.authorZhang, Quanjun
dc.contributor.authorYang, Huaqiang
dc.contributor.authorZou, Qingjian
dc.contributor.authorLai, Chengdan
dc.contributor.authorJiang, Fei
dc.contributor.authorZhao, Ping
dc.contributor.authorLuo, Zhiwei
dc.contributor.authorYang, Jiayin
dc.contributor.authorChen, Qian
dc.contributor.authorWang, Yan
dc.contributor.authorNewsome, Philip N
dc.contributor.authorFrampton, Jon
dc.contributor.authorMaxwell, Patrick H
dc.contributor.authorLi, Wenjuan
dc.contributor.authorChen, Shuhan
dc.contributor.authorWang, Dongye
dc.contributor.authorSiu, Tak-Shing
dc.contributor.authorTam, Sidney
dc.contributor.authorTse, Hung-Fat
dc.contributor.authorQin, Baoming
dc.contributor.authorBao, Xichen
dc.contributor.authorEsteban, Miguel A
dc.contributor.authorLai, Liangxue
dc.date.accessioned2019-03-07T14:24:47Z
dc.date.available2019-03-07T14:24:47Z
dc.date.issued2017-03-17
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290299
dc.description.abstractHereditary 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.
dc.description.sponsorshipWellcome Trust
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLiver
dc.subjectKidney
dc.subjectHepatocytes
dc.subjectAnimals
dc.subjectRabbits
dc.subjectHumans
dc.subjectLiver Failure
dc.subjectTyrosinemias
dc.subjectDisease Models, Animal
dc.subjectHydrolases
dc.subjectFemale
dc.subjectMale
dc.subjectGene Knockout Techniques
dc.titleFumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.
dc.typeArticle
prism.endingPage4763
prism.issueIdentifier11
prism.publicationDate2017
prism.publicationNameJ Biol Chem
prism.startingPage4755
prism.volume292
dc.identifier.doi10.17863/CAM.37527
dcterms.dateAccepted2017-01-03
rioxxterms.versionofrecord10.1074/jbc.M116.764787
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-03
dc.contributor.orcidMaxwell, Patrick [0000-0002-0338-2679]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (096956/Z/11/Z)
cam.issuedOnline2017-01-04


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International