Résumé
Crigler-Najjar syndrome (CN) is a rare recessive autosomal disease characterized by the mutation of the gene encoding for the hepatic uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) enzyme. Depending on the enzyme activity, two types of the syndrome can be identified: the enzyme is totally absent (type I) or its activity is decreased (type II). The symptoms of this metabolic disorder start early in life by a cutaneous jaundice and eventually lead to severe unconjugated hyperbilirubinemia that can cause irreversible neurological injury and death. The only curative treatment is currently the liver transplantation. The other available treatments can only manage symptoms and their efficacy tends to decrease overtime. Genethon has developed a liver gene therapy with adeno-associated virus (AAV) vectors to treat the Crigler-Najjar patients in an international clinical trial. Based on the promising first results, serum bilirubin levels could be significantly reduced by the UGT1A1 transgene. However, a long- term follow-up is required by the competent authorities to fully assess the safety profile of the therapy. The purpose of this thesis is to display the risk-benefit balance at stake in the gene therapy of the Crigler-Najjar syndrome.