Strategies for hepatic gene therapy

GENE AUGMENTATION THERAPY

This strategy involves administration of a normal gene to replace a missing or dysfunctional gene product resulting from a defective gene, as has been illustrated by studies on the hereditary disorder familial hypercholesterolaemia. In this disease, a defect in the low density lipoprotein (LDL) receptor gene results in abnormal expression of the LDL receptor and consequent failure of clearance of LDL cholesterol.1 Using an animal model of familial hypercholesterolaemia, the Watanabe heritable hyperlipidaemic (WHHL) rabbit, investigators have been able to show the successful transduction of a functional rabbit LDL gene into target hepatocytes. This resulted in a 30–40% reduction in serum cholesterol, with the recombinant LDL receptor being detectable for up to six months.2 In clinical trials, five patients homozygous for familial hypercholesterolaemia underwent ex vivo replacement of the faulty gene.3 This was achieved by segmental hepatic resection, preparation of hepatocyte cultures, and transduction of these cultures with a recombinant retrovirus encoding the gene for the human LDL receptor. The genetically modified cells were then transplanted into the liver using portal venous cannulation. Prolonged reductions in LDL cholesterol were seen in three of the five patients, and this procedure was remarkably free of any major side effects. This study served to demonstrate the feasibility of ex …