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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:435.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Complete Atherosclerosis Regression After Human ApoE Gene Transfer in ApoE-Deficient/Nude Mice

Caroline Desurmont; Jean-Michel Caillaud; Florence Emmanuel; Patrick Benoit; Jean Charles Fruchart; Graciela Castro; Didier Branellec; Jean-Michel Heard; Nicolas Duverger

From the Laboratoire RTG, (C.D., J.-M.H.), Institut Pasteur, Paris; the Cardiovascular Department, Rhône-Poulenc Rorer/Gencell (J.-M.C., F.E., P.B., D.B., N.D.), Vitry/Seine; and the Laboratoire INSERM U325 (J.C.F., G.C.), Institut Pasteur de Lille, Lille, France.

Correspondence to Nicolas Duverger, PhD, Cardiovascular Department, Rhône-Poulenc Rorer/Gencell, 13, quai Jules Guesde, 94403 Vitry/Seine cedex, France. E-mail nicolas.duverger{at}aventis.com

Abstract—The apolipoprotein E (apoE)-deficient mouse is a relevant animal model of human atherosclerosis. Although the prevention of atherosclerosis development has been documented after somatic gene transfer into animal models, regression of lesions remains to be demonstrated. Thus, we used this genetically defined mouse model nn the nude background to show atherosclerosis regression. ApoE-deficient nude mice were infected with 5x10⁸ or 10⁹ plaque-forming units of a first-generation adenovirus encoding human apoE cDNA. The secretion of human apoE resulted in a rapid decrease of total cholesterol, which normalized the hypercholesterolemic phenotype within 14 days (from 600±100 to <100 µg/mL). Transgene expression was observed during a period of >4 months, with a normalization of cholesterol and triglyceride levels during 5 months. At that time, we successfully reinjected the recombinant adenovirus and observed the appearance of the human protein as well as the correction of lipoprotein phenotype. In mice killed 6 months-after the first infection, we observed a dose-dependent regression of fatty streak lesions in the aorta. We showed sustained expression of a transgene with a first-generation adenoviral vector and a correction of dyslipoproteinemia phenotype leading to lesion regression. These data demonstrate that somatic gene transfer can induce plaque regression.

Key Words: atherosclerosis • regression • gene transfer • adenoviral vector • apolipoprotein

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