SAFETY AND FEASIBILITY OF LIVER-DIRECTED EX-VIVO GENE-THERAPY FOR HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Objective The purpose of this report was to provide detailed informati on on the safety and feasibility of surgical procedures associated wit h the first ex vivo liver-directed gene therapy trial for the treatmen t of familial hypercholesterolemia (FH). Summary Background Data Famil ial hypercholesterolemia is an autosomal dominant disease in which the gene encoding the low density lipoprotein receptor is defective. Pati ents homozygous for this mutation have extraordinarily high levels of cholesterol and accelerated atherosclerosis and die prematurely of myo cardial infarction. The concept of liver-directed gene therapy was bas ed on the report of normalization of cholesterol levels by orthotopic cardiac/liver transplant in a child with homozygous FH. Methods Five p atients with homozygous FH were selected for inclusion in this trial. The patients underwent hepatic resection and placement of a portal ven ous catheter. Primary hepatocytes cultures were prepared from the rese cted liver and transduced with a recombinant retrovirus encoding the g ene for the human low density lipoprotein receptor. The genetically mo dified cells were then transplanted into the liver through the portal venous catheter. Results Numerous clinical, laboratory, and radiologic parameters were analyzed. Elevations of the hepatic transaminases and leukocyte counts and a decline in hematocrit count were noted. Transi ent elevations of the portal pressure were observed during cell infusi on. No major perioperative morbidity-specifically, myocardial infarct, perioperative hemorrhage, or portal vein thrombosis-or death occurred as a result of this protocol. Conclusion Liver-directed ex vivo gene therapy can be accomplished safely in humans and is appropriate for se lected patients.