Adenovirus-Mediated Gene Therapy in a Mouse Model of Hereditary Tyrosinemia Type I

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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. In this study, we tested the effectiveness of a fumarylacetoacetate hydrolase (FAH)-expressing adenovirus in the treatment of a mouse model of the human disease hereditary tyrosinemia type I (HT1). Thirteen mice were treated with the recombinant adenovirus and analyzed at intervals ranging from 2 to 9 months after injection. All treated mice had improved survival, weight gain, and liver function tests. A high percentage (>20%) of hepatic cells remained FAH-positive, even 6–9 months post injection. However, 9 of 13 mice developed either microscopic or macroscopic hepatocellular carcinomas originating from nontransduced FAH-negative cells. This report demonstrates that adenoviral gene therapy of HT1 is aided by the strong selective advantage of FAH-expressing cells, but also that adenoviral gene therapy does not obviate the tumor risk inherent in HT1.