ADENOVIRUS-MEDIATED GENE-THERAPY IN A MOUSE MODEL OF HEREDITARY TYROSINEMIA TYPE-I

Mice lacking the enzyme fumarylacetoacetate hydrolase (FAH) have sympt oms similar to humans with the disease hereditary tyrosinemia type I ( HT1). FAH-deficient mice were injected with a first-generation adenovi ral vector expressing the human FAH gene and followed for up to 9 mont hs. Nontreated FAH mutant control mice died within 6 weeks from fulmin ant liver failure, whereas FAH adenovirus-infected animals survived un til sacrifice at 2-9 months. Nine of 13 virus-treated animals develope d hepatocellular cancer. Immunohistochemical analysis revealed a mosai c of FAH-deficient and FAH-positive cells in all animals and liver fun ction tests were improved compared to controls. Even mice harvested 9 months after viral infection had >50% FAH-positive cells. These result s demonstrate the strong selective advantage of FAH-expressing cells i n an FAH-deficient liver but also illustrate the danger of carcinomas arising from FAH-deficient hepatocytes in HT1.