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Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1

Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver dis...

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Autores principales: Hickey, Raymond D., Nicolas, Clara T., Allen, Kari, Mao, Shennen, Elgilani, Faysal, Glorioso, Jaime, Amiot, Bruce, VanLith, Caitlin, Guthman, Rebekah, Du, Zeji, Chen, Harvey, Harding, Cary O., Kaiser, Robert A., Nyberg, Scott L., Lillegard, Joseph B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322137/
https://www.ncbi.nlm.nih.gov/pubmed/30477316
http://dx.doi.org/10.1177/0963689718814188
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author Hickey, Raymond D.
Nicolas, Clara T.
Allen, Kari
Mao, Shennen
Elgilani, Faysal
Glorioso, Jaime
Amiot, Bruce
VanLith, Caitlin
Guthman, Rebekah
Du, Zeji
Chen, Harvey
Harding, Cary O.
Kaiser, Robert A.
Nyberg, Scott L.
Lillegard, Joseph B.
author_facet Hickey, Raymond D.
Nicolas, Clara T.
Allen, Kari
Mao, Shennen
Elgilani, Faysal
Glorioso, Jaime
Amiot, Bruce
VanLith, Caitlin
Guthman, Rebekah
Du, Zeji
Chen, Harvey
Harding, Cary O.
Kaiser, Robert A.
Nyberg, Scott L.
Lillegard, Joseph B.
author_sort Hickey, Raymond D.
collection PubMed
description Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson’s trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.
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spelling pubmed-63221372019-01-14 Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1 Hickey, Raymond D. Nicolas, Clara T. Allen, Kari Mao, Shennen Elgilani, Faysal Glorioso, Jaime Amiot, Bruce VanLith, Caitlin Guthman, Rebekah Du, Zeji Chen, Harvey Harding, Cary O. Kaiser, Robert A. Nyberg, Scott L. Lillegard, Joseph B. Cell Transplant Original Articles Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson’s trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1. SAGE Publications 2018-11-26 2019-01 /pmc/articles/PMC6322137/ /pubmed/30477316 http://dx.doi.org/10.1177/0963689718814188 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Articles
Hickey, Raymond D.
Nicolas, Clara T.
Allen, Kari
Mao, Shennen
Elgilani, Faysal
Glorioso, Jaime
Amiot, Bruce
VanLith, Caitlin
Guthman, Rebekah
Du, Zeji
Chen, Harvey
Harding, Cary O.
Kaiser, Robert A.
Nyberg, Scott L.
Lillegard, Joseph B.
Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title_full Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title_fullStr Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title_full_unstemmed Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title_short Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
title_sort autologous gene and cell therapy provides safe and long-term curative therapy in a large pig model of hereditary tyrosinemia type 1
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322137/
https://www.ncbi.nlm.nih.gov/pubmed/30477316
http://dx.doi.org/10.1177/0963689718814188
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