RT Journal Article SR Electronic T1 In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.01.02.425079 DO 10.1101/2021.01.02.425079 A1 Clara T Nicolas A1 Caitlin J VanLith A1 Kari L Allen A1 Raymond D Hickey A1 Zeji Du A1 Lori G Hillin A1 Rebekah M Guthman A1 William J Cao A1 Aditya Bhagwate A1 Daniel O’Brien A1 Jean-Pierre Kocher A1 Robert A Kaiser A1 Stephen J Russell A1 Joseph B Lillegard YR 2021 UL http://biorxiv.org/content/early/2021/03/16/2021.01.02.425079.abstract AB Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.Competing Interest StatementThe authors have declared no competing interest.