THERAPEUTIC TRIALS IN THE MURINE MODEL OF HEREDITARY TYROSINEMIA TYPE-I - A PROGRESS REPORT

We have studied a knockout mouse with fumarylacetoacetate hydrolase (F AH) deficiency as a model of human hereditary tyrosinaemia type I (HT1 ). These mice have a phenotype very similar to the human disease, whic h is characterized by acute hepatic failure, renal tubular disease and hepatocarcinoma. We have previously reported on the efficacy of tro-4 -trifiuoromethylbenzyol)-1,3-cyclohexanedione (NTBC) in preventing acu te liver disease in HT1 mice. Here we present a progress report on lon g-term follow up (>1 year) of high-dose NTBC therapy in combination wi th tyrosine restriction. In vivo retroviral gene therapy was also effe ctive in abolishing the acute liver failure of HT1. Retrovirally treat ed mice remained completely healthy and active for 12 months after ret roviral gene transfer. However, hepatocarcinoma developed in 2/3 treat ed animals after 1 year. Southern blot analysis showed that the tumour s did not arise from retrovirally transduced hepatocytes but from non- corrected FAH-deficient cells. These results highlight the extreme dan ger for tumour formation in HT1 and indicate the need for improved gen e therapy that leads to the elimination of endogenous FAH-deficient li ver cells.