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(Circulation. 2001;103:1274.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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

Kazuhiro Oka, PhD; Lucio Pastore, MD, PhD; In-Hoo Kim, MD, PhD; Aksam Merched, PhD; Shuichi Nomura, MD, PhD; Hye-Jeong Lee, PhD; Maria Merched-Sauvage, MS; Celeste Arden-Riley, BS; Brendan Lee, MD, PhD; Milton Finegold, MD; Arthur Beaudet, MD; Lawrence Chan, MBBS, DSc

From the Departments of Molecular and Cellular Biology (K.O., I.-H.K., A.M., S.N., H.-J.L., M.M.-S., C.A.-R., L.C.), Molecular and Human Genetics (L.P., B.L., A.B.), Pathology (M.F.), and Medicine (L.C.), Baylor College of Medicine, Houston, Texas.

Correspondence to Dr Lawrence Chan, Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail lchan{at}bcm.tmc.edu

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.

Key Words: genes • adenovirus • receptors • lipoproteins • hypercholesterolemia

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