In summary, our results suggest that the intravenous injection in mice of a low dose of an AAV8-based vector encoding the LDLR cDNA generates sustained expression of the LDLR protein in the liver without evidence of hepatic inflammation or toxicity and is highly effective in markedly reducing plasma cholesterol levels and regressing atherosclerosis in a “humanized” murine model of hoFH. This evidence concerns the gene LDLR and homozygous familial hypercholesterolemia.