Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I
Abstract
Current strategies for hepatic gene therapy are either quantitatively inefficient or suffer from lack of permanent gene expression. We have utilized an animal model of hereditary tyrosinaemia type I (HT1), a recessive liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH), to determine whether in vivo selection of corrected hepatocytes could improve the efficiency of liver gene transfer. As few as 1,000 transplanted wild-type hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections >90% of hepatocytes became FAH positive and liver function was restored to normal. Our results demonstrate that in vivo selection is a useful strategy for hepatic gene therapy and may lead to effective treatment of human HT1 by retroviral gene transfer.
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FAH deficiency results in the accumulation of fumarylacetoacetate, maleylacetoacetate, and succinylacetone in the liver and kidney, which is believed to be responsible for certain pathological aspects of HT1.
“FAH deficiency results in the accumulation of fumarylacetoacetate, maleylacetoacetate, and succinylacetone (SA) in the liver and kidney, which is believed to be responsible for certain pathological aspects of the disorder (2, 3).”
From Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1 (2001) · cites this paper as [3]
Strong positive selection for FAH+ cells in the HTI mouse liver has been demonstrated.
“Strong positive selection for FAH+ cells in the HTI mouse liver has been demonstrated24”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [24]
When AAV vectors containing genomic Fah sequence are administered to Fah5981SB mice, only corrected FAH+ hepatocytes that have undergone integration by homologous recombination can survive and repopulate the liver.
“In this system, when AAV vectors containing genomic Fah sequence (hereafter referred to as AAV-Fah) are administered to Fah5981SB mice, only corrected FAH-positive (FAH+) hepatocytes that have undergone integration by homologous recombination can survive and repopulate the liver.”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [24]
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Self-citation
- Authors
- Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.-N., Finegold, M., & Grompe, M.
- Affiliations
- Oregon Health & Science University (US)
- Université Laval (CA)
- National Institutes of Health (US)
- Texas Children's Hospital (US)
- Venue
- Nature Genetics
- Published
- 1996-03-01
- Volume
- 12
- Issue
- 3
- Pages
- 266-273
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1995612506
- Semantic Scholar
- adc269e15f47a3bf4d815f14b8a3d1ef31296f9b
- Cited by
- 549
- References
- 55
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 11 · 2022: 17 · 2021: 12 · 2020: 11 · 2019: 11 · 2018: 24 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 18 · 2013: 17 · 2012: 30
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Update notices
- correction (1996-04-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, DK48252)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- fumarylacetoacetate hydrolase, hepatocyte transplantation, in vivo selection, retroviral gene transfer, liver-directed gene therapy, liver regeneration
- MeSH terms
- Amino Acid Metabolism, Inborn Errors, Animals, Cell Count, Cyclohexanones, Disease Models, Animal, Enzyme Inhibitors, Humans, Hydrolases, Immunoenzyme Techniques, Liver, Liver Function Tests, Liver Neoplasms, Male, Mice, Inbred C57BL, Nitrobenzoates, Retroviridae, Tyrosine, Genetic Therapy, Cell Transplantation, Mice
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