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

Clara T. Nicolas, Caitlin J. VanLith, Raymond D. Hickey, Zeji Du, Lori G. Hillin, Rebekah M. Guthman, William J. Cao, Benjamin Haugo, Annika Lillegard, Diya Roy, Aditya Bhagwate, Daniel O’Brien, Jean-Pierre Kocher, Robert A. Kaiser, Stephen J. Russell and Joseph B. Lillegard ()
Additional contact information
Clara T. Nicolas: Mayo Clinic
Caitlin J. VanLith: Mayo Clinic
Raymond D. Hickey: Mayo Clinic
Zeji Du: Mayo Clinic
Lori G. Hillin: Mayo Clinic
Rebekah M. Guthman: Mayo Clinic
William J. Cao: Mayo Clinic
Benjamin Haugo: Mayo Clinic
Annika Lillegard: Mayo Clinic
Diya Roy: Mayo Clinic
Aditya Bhagwate: Mayo Clinic
Daniel O’Brien: Mayo Clinic
Jean-Pierre Kocher: Mayo Clinic
Robert A. Kaiser: Mayo Clinic
Stephen J. Russell: Mayo Clinic
Joseph B. Lillegard: Mayo Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32576-7

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