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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, Kari L Allen, Raymond D Hickey, Zeji Du, Lori G Hillin, Rebekah M Guthman, William J Cao, Aditya Bhagwate, Daniel O’Brien, Jean-Pierre Kocher, Robert A Kaiser, Stephen J Russell, Joseph B Lillegard
doi: https://doi.org/10.1101/2021.01.02.425079
Clara T Nicolas
1Department of Surgery, Mayo Clinic, Rochester, MN
2Faculty of Medicine, University of Barcelona, Barcelona, Spain
3Department of Surgery, University of Alabama Birmingham, Birmingham, AL
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Caitlin J VanLith
1Department of Surgery, Mayo Clinic, Rochester, MN
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Kari L Allen
1Department of Surgery, Mayo Clinic, Rochester, MN
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Raymond D Hickey
1Department of Surgery, Mayo Clinic, Rochester, MN
4Department of Molecular Medicine, Mayo Clinic, Rochester, MN
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Zeji Du
1Department of Surgery, Mayo Clinic, Rochester, MN
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Lori G Hillin
1Department of Surgery, Mayo Clinic, Rochester, MN
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Rebekah M Guthman
1Department of Surgery, Mayo Clinic, Rochester, MN
5Medical College of Wisconsin, Wausau, WI
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William J Cao
1Department of Surgery, Mayo Clinic, Rochester, MN
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Aditya Bhagwate
6Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
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Daniel O’Brien
6Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
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Jean-Pierre Kocher
6Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
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Robert A Kaiser
1Department of Surgery, Mayo Clinic, Rochester, MN
7Midwest Fetal Care Center, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN
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Stephen J Russell
4Department of Molecular Medicine, Mayo Clinic, Rochester, MN
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Joseph B Lillegard
1Department of Surgery, Mayo Clinic, Rochester, MN
7Midwest Fetal Care Center, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN
8Pediatric Surgical Associates, Minneapolis, MN
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  • For correspondence: jlillegard@msn.com
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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 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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 16, 2021.
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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, Kari L Allen, Raymond D Hickey, Zeji Du, Lori G Hillin, Rebekah M Guthman, William J Cao, Aditya Bhagwate, Daniel O’Brien, Jean-Pierre Kocher, Robert A Kaiser, Stephen J Russell, Joseph B Lillegard
bioRxiv 2021.01.02.425079; doi: https://doi.org/10.1101/2021.01.02.425079
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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, Kari L Allen, Raymond D Hickey, Zeji Du, Lori G Hillin, Rebekah M Guthman, William J Cao, Aditya Bhagwate, Daniel O’Brien, Jean-Pierre Kocher, Robert A Kaiser, Stephen J Russell, Joseph B Lillegard
bioRxiv 2021.01.02.425079; doi: https://doi.org/10.1101/2021.01.02.425079

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