Correction of fumarylacetoacetate hydrolase deficiency (type I tyrosinemia) in cultured human fibroblasts by retroviral-mediated gene transfer.

Type I hereditary tyrosinemia results from an inherited deficiency in fumarylacetoacetate hydrolase, the enzyme involved in the last step in tyrosine catabolic pathway. The cloning of the cDNA encoding FAH in human has opened the way to genetic treatment of HT 1. We have constructed recombinant retroviral vectors carrying the cDNA encoding human FAH. In the present report we show that these vectors are able to restore FAH activity stably in primary fibroblasts from HT 1 patients and at high level. The possibility to express FAH stably in deficient patients represents a first step towards future gene therapy for type I hereditary tyrosinemia and may help to decipher the pathogenesis of the disease at the molecular level.