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-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--a model which is most adequately mimicking the clinical setting.


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.


CONCLUSIONS
Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.
Lebherz
Corinna
C
Department of Pathology and Laboratory Medicine, Gene Therapy Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. corinna.lebherz@med.uni-muenchen.de
Sanmiguel
Julio
J
Wilson
James M
JM
Rader
Daniel J
DJ
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000517:prevention & control; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods
D016632:Apolipoprotein A-I; D011973:Receptors, LDL