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Background  The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-I M ) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice – a model which is most adequately mimicking the clinical setting.    Methods and results  Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-I M  or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic  en face  analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-I M  by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.    Conclusion  Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-I M  each significantly reduced atherosclerosis progression to a similar extent.

Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent