Therapeutic approach to familial hypercholesterolemia by HVJ-liposomes in LDL receptor knockout mouse.

Familial hypercholesterolemia (FH) is an inherited disease in humans, which we have used as a model to develop a new strategy of gene therapy. This disease, which is due to mutation in the low density lipoprotein (LDL) receptor gene and results in deficiency of the LDL receptor, is associated with hypercholesterolemia and premature development of coronary heart disease. This disease has been identified as one of the target diseases for gene therapy, because a 50% reduction of cholesterol level would be beneficial in such patients. In this study, we examined the feasibility of gene therapy by the delivery of the human LDL receptor plasmid into the liver via the portal vein. For gene transfer we utilized HVJ-liposome method with which many successful gene transfers have been reported. Administration of the human LDL receptor plasmid by the HVJ-liposome method into the liver resulted in a decrease of total cholesterol level. Moreover, second administration of this gene two weeks after the first administration resulted in sustained lowering of total cholesterol level. Although single administration of plasmid by the HVJ-liposome method induced antibodies against HVJ, this antibody production did not affect gene expression following second administration. These results suggest the possibility of a novel repetitive gene therapy for FH, using human LDL receptor plasmid transfer directly into the liver by the HVJ-liposome method.