Complete and permanent correction of hyperbilirubinemia in newborn Gunn rats by lentiviral-mediated gene transfer

Background: Crigler Najjar type 1 disease (CN1) is a rare inherited metabolic disease characterized by complete absence of hepatic UDP-Glucuronosyl transferase (UGT1A1, EC 2.4.1.17). The hallmark of CN1 is a very high level of circulating unconjugated bilirubin that may result in kernicterus. The only curative treatment of CN1 is orthotopic liver transplantation. The Gunn rat is the model for CN1 and many previous studies have attempted to correct hyperbilirubinemia in the Gunn rat using a large array of gene transfer vectors. However in most cases phenotypic correction was transient, mainly because of immune response directed against the transduced cells. Here we show that in vivo neonatal hepatocyte transduction with lentiviral vectors resulted in long-term complete phenotype correction in Gunn rats.