title: Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.
abstract: Mice lacking the enzyme fumarylacetoacetate hydrolase (FAH) have symptoms similar to humans with the disease hereditary tyrosinemia type I (HT1). FAH-deficient mice were injected with a first-generation adenoviral vector expressing the human FAH gene and followed for up to 9 months. Nontreated FAH mutant control mice died within 6 weeks from fulminant liver failure, whereas FAH adenovirus-infected animals survived until sacrifice at 2-9 months. Nine of 13 virus-treated animals developed hepatocellular cancer. Immunohistochemical analysis revealed a mosaic of FAH-deficient and FAH-positive cells in all animals and liver function tests were improved compared to controls. Even mice harvested 9 months after viral infection had > 50% FAH-positive cells. These results demonstrate the strong selective advantage of FAH-expressing cells in an FAH-deficient liver but also illustrate the danger of carcinomas arising from FAH-deficient hepatocytes in HT1.
authors.affiliation: Medical and Molecular Genetics Department, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: K
authors.initials: K
authors.lastname: Overturf
authors.forename: M
authors.initials: M
authors.lastname: al-Dhalimy
authors.forename: C N
authors.initials: CN
authors.lastname: Ou
authors.forename: M
authors.initials: M
authors.lastname: Finegold
authors.forename: R
authors.initials: R
authors.lastname: Tanguay
authors.forename: A
authors.initials: A
authors.lastname: Lieber
authors.forename: M
authors.initials: M
authors.lastname: Kay
authors.forename: M
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular / Q000821:virology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D006867:Hydrolases / Q000172:deficiency* / Q000235:genetics; D008113:Liver Neoplasms / Q000821:virology; D051379:Mice; D014443:Tyrosine / Q000097:blood / Q000172:deficiency*
chemical_list: D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase