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

• Published in: Nature communications Vol. 13; no. 1; p. 5012
• Main Authors: Nicolas, Clara T., VanLith, Caitlin J., Hickey, Raymond D., Du, Zeji, Hillin, Lori G., Guthman, Rebekah M., Cao, William J., Haugo, Benjamin, Lillegard, Annika, Roy, Diya, Bhagwate, Aditya, O’Brien, Daniel, Kocher, Jean-Pierre, Kaiser, Robert A., Russell, Stephen J., Lillegard, Joseph B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/44; 13/51; 38/22; 38/23; 38/39; 38/77; 38/90; 38/91; 692/699/317; 692/700/565/201; Animal diseases; Animal models; Animals; Cell therapy; Fibrosis; Fumarylacetoacetase; Gene expression; Gene therapy; Genomics; Hereditary tyrosinemia type 1; Humanities and Social Sciences; Inborn errors of metabolism; Liver; Liver diseases; multidisciplinary; Portal vein; Science; Science (multidisciplinary); Swine; Tumorigenicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32576-7

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 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 is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays 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. Hereditary tyrosinemia type 1 (HT1) is an inborn error of metabolism caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Here, the authors show in an animal model that HT1 can be treated via in vivo portal vein administration of a lentiviral vector carrying the human FAH transgene.