Complete atherosclerosis regression after human ApoE gene transfer in ApoE-deficient/nude mice

The apolipoprotein E (apoE)-deficient mouse is a relevant animal model of h uman atherosclerosis. Although the prevention of atherosclerosis developmen t has been documented after somatic gene transfer into animal models, regre ssion of lesions remains to be demonstrated. Thus, we used this genetically defined mouse model nn the nude background to show atherosclerosis regress ion. ApoE-deficient nude mice were infected with 5x10(8) or 10(9) plaque-fo rming 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 60 0+/-100 to <100 mu g/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 a denovirus and observed the appearance of the human protein as well as the c orrection 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-g eneration adenoviral vector and a correction of dyslipoproteinemia phenotyp e leading to lesion regression. These data demonstrate that somatic gene tr ansfer can induce plaque regression.