In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

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. Overall design: 23 samples were analyzed. WT animal RNA expression profiles were compared to animals treated with the standard of care for HT1: NTBC, as well as LV-FAH gene therapy, and the negative control, which was cycled on and off the standard of care NTBC. Samples were also analyzed for integration profiles of LV-FAH from various tissues in the LV-FAH treated animals. ****Please note that raw data for the '282 NTBC RNA-Seq', '266 RNA-seq (RLI)' samples are unavailable and thus are not included in the records****