GENE THERAPY FOR INBORN ERRORS OF LIVER METABOLISM

Inborn errors of liver metabolism are frequent causes of morbidity and mortality especially in children. For several of these diseases, treatment approaches depend on the manipulation of the affected metabolic pathway by diet, drugs, vitamin cofactors, enzyme induction, end-product replacement, and alternative pathway activation. Unfortunately, these approaches often remain unsatisfactory especially in the face of illness or catabolism. Ideally, transfer of the normal genes in the liver cells that are defective might restore the metabolic function. The goal of our proposal is to design and to investigate gene-based therapeutic strategies to correct inborn errors of liver metabolism. We focused our attention on Crigler-Najjar syndrome as a disease model. Patients with this disease are at risk of life-threatening elevations of bilirubin, and they generally sleep and spend extended hours under bilirubin lights throughout childhood and adolescence. Despite this therapy, they remain at risk of brain damage when intercurrent infections may increase production of bilirubin above that which can be controlled by the bilirubin light therapy. Thus, patients with Crigler-Najjar type I often are advised to consider liver transplantation. We feel that the alternative therapy of liver transplantation has sufficient risk to make the attempt of hepatocyte gene therapy justifiable from the perspective of risk: benefit ratio and for this reason we have selected Crigler-Najjar type I for our studies.