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

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.