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

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The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) 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 ├óÔé¼ÔÇ£ 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-IM 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-IM by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.

Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.

Apolipoprotein A-I (wtApoA-I) is the primary protein component of high density lipoproteins (HDL) [1] and like HDL cholesterol is inversely associated with atherosclerotic cardiovascular disease. Transgenic overexpression of wtApoA-I in liver substantially reduces progression of atherosclerosis in mice [2,3] and rabbits [4]. Furthermore, somatic gene transfer of wtApoA-I to liver using adenoviral vectors reduces progression [5,6] and induces regression [7] of atherosclerosis.


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