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

• DOI: 10.1161/01.cir.103.9.1274
• Publication Date: 2012-06-12T00:09:32Z
• Authors: Kazuhiro Oka; Lucio Pastore; In-Hoo Kim; Aksam Merched; Shuichi Nomura; Hye-Jeong Lee; Maria Merched-Sau...; Celeste Arden-Riley; Brendan Lee; Milton Finegold; Arthur Beaudet; Lawrence Chan
• Keywords: Mice, Knockout; 0301 basic medicine; Time Factors; Arteriosclerosis; Lipoproteins; Genetic Vectors; Gene Transfer Techniques; Gene Expression; Adenoviridae; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cholesterol; Receptors, LDL; Animals; Female; Tissue Distribution; RNA, Messenger; Transgenes; Helper Viruses; Plasmids

Background —Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects ≈1 in 500 persons in the heterozygous state and ≈1 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) 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 ≥6 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.