Long-term stable correction of low-density lipoprotein receptor-deficient mice with a helper-dependent adenoviral vector expressing the very low-density lipoprotein receptor

Background-Familial hypercholesterolemia (FH) that results from LDL recepto r (LDLR) deficiency affects approximate to1 in 500 persons in the heterozyg ous state and approximate to 1 in 1 million persons in the homozygous state . We tested a novel gene therapy strategy for the treatment of FH in a mous e model. Methods and Results-We delivered the VLDL receptor (VLDLR) to the liver of LDLR-deficient mice and compared the effect of a helper-dependent adenovira l vector with all viral coding sequences deleted (HD-Ad-mVLDLR) with a firs t-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no ex pression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted greate r than or equal to6 months. Acute liver toxicity (as measured with liver en zyme elevation) occurred after FG-Ad-mVLDLR but not after HD-Ad-mVLDLR, HD- Ad-0, or DB treatment. At 6 months, VLDLR was detected in the liver with We stern blotting and with immunofluorescence staining only in HD-Ad-mVLDLR-tr eated mice. Aortic atherosclerosis was almost completely prevented in these animals. Conclusions-HD-Ad-mediated intravenous delivery of VLDLR to hepatocytes is well tolerated. It produces long-term lowering of plasma cholesterol and pr events atherosclerosis development in LDLR-deficient mice. These data provi de support for the feasibility and safety of this approach for therapy of h uman subjects.