HEPATOCYTES CORRECTED BY GENE-THERAPY ARE SELECTED IN-VIVO IN A MURINE MODEL OF HEREDITARY TYROSINEMIA TYPE-I

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 re cessive liver disease caused by deficiency of fumarylacetoacetate hydr olase (FAH), to determine whether in vivo selection of corrected hepat ocytes could improve the efficiency of liver gene transfer. As few as 1,000 transplanted wild-type hepatocytes were able to repopulate mutan t liver, demonstrating their strong competitive growth advantage. Muta nt 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 selectio n is a useful strategy for hepatic gene therapy and may lead to effect ive treatment of human HT1 by retroviral gene transfer.