Long-Term Stable Correction of Low-Density Lipoprotein Receptor-Deficient Mice With a Helper-Dependent Adenoviral Vector Expressing the Very Low-Density Lipoprotein Receptor

K. Oka, L. Pastore, I.-H. Kim, A. Merched, S. Nomura, H.-J. Lee, M. Merched-Sauvage, C. Arden-Riley, B. Lee, M. Finegold, A. Beaudet, L. Chan
2001 Circulation  
Background-Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects Ϸ1 in 500 persons in the heterozygous state and Ϸ1 in 1 million persons in the homozygous state. We tested a novel gene therapy strategy for the treatment of FH in a mouse 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 adenoviral vector with all viral coding sequences deleted (HD-Ad-mVLDLR)
more » ... (HD-Ad-mVLDLR) with a first-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no expression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted Ն6 months. Acute liver toxicity (as measured with liver enzyme 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 Western blotting and with immunofluorescence staining only in HD-Ad-mVLDLR-treated 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 prevents atherosclerosis development in LDLR-deficient mice. These data provide support for the feasibility and safety of this approach for therapy of human subjects. (Circulation. 2001;103:1274-1281.)
doi:10.1161/01.cir.103.9.1274 pmid:11238273 fatcat:itnzgsw7cvg7dgfl762mus4p4y