PT  - JOURNAL ARTICLE
AU  - Clara T Nicolas
AU  - Caitlin J VanLith
AU  - Kari L Allen
AU  - Raymond D Hickey
AU  - Zeji Du
AU  - Lori G Hillin
AU  - Rebekah M Guthman
AU  - William J Cao
AU  - Aditya Bhagwate
AU  - Daniel O’Brien
AU  - Jean-Pierre Kocher
AU  - Robert A Kaiser
AU  - Stephen J Russell
AU  - Joseph B Lillegard
TI  - <em>In vivo</em> lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions
AID  - 10.1101/2021.01.02.425079
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.02.425079
4099  - http://biorxiv.org/content/early/2021/03/16/2021.01.02.425079.short
4100  - http://biorxiv.org/content/early/2021/03/16/2021.01.02.425079.full
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.