Therapeutic trials in the murine model of hereditary tyrosinaemia type I: a progress report.

We have studied a knockout mouse with fumarylacetoacetate hydrolase (FAH) deficiency as a model of human hereditary tyrosinaemia type (I (HT1). These mice have a phenotype very similar to the human disease, which is characterized by acute hepatic failure, renal tubular disease and hepatocarcinoma. We have previously reported on the efficacy of 2-(2-nitro-4-trifluoromethylbenzyol)-1,3-cyclohexanedione (NTBC) in preventing acute liver disease in HT1 mice. Here we present a progress report on long-term follow up (> 1 year) of high-dose NTBC therapy in combination with tyrosine restriction. In vivo retroviral gene therapy was also effective in abolishing the acute liver failure of HT1. Retrovirally treated mice remained completely healthy and active for 12 months after retroviral gene transfer. However, hepatocarcinoma developed in 2/3 treated animals after 1 year. Southern blot analysis showed that the tumours did not arise from retrovirally transduced hepatocytes but from non-corrected FAH-deficient cells. These results highlight the extreme danger for tumour formation in HT1 and indicate the need for improved gene therapy that leads to the elimination of endogenous FAH-deficient liver cells.