Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E

被引：0
作者：
JD Harris
S Schepelmann
T Athanasopoulos
IR Graham
AK Stannard
Z Mohri
V Hill
DG Hassall
JS Owen
G Dickson
机构：
[1] Centre for Biomedical Research,Department of Medicine
[2] School of Biological Sciences,undefined
[3] Royal Holloway,undefined
[4] University of London,undefined
[5] Centre of Hepatology,undefined
[6] Royal Free and University College Medical School,undefined
[7] GlaxoSmithKline,undefined
[8] Medicines Research Centre,undefined
来源：
Gene Therapy | 2002年 / 9卷
关键词：
gene therapy; apolipoprotein E; atherosclerosis; AAV;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Apolipoprotein E (apoE) is a multifunctional plasma glycoprotein involved in lipoprotein metabolism and a range of cell signalling phenomena. ApoE-deficient (apoE-/-) mice exhibit severe hypercholesterolaemia and are an excellent model of human atherosclerosis. ApoE somatic gene transfer and bone marrow transplantation in apoE-/- mice results in reversal of hypercholesterolaemia, inhibition of atherogenesis and regression of atherosclerotic plaque density. Replication defective adeno-associated virus vectors (rAAVs) are an attractive system currently in clinical trial for muscle-based heterologous gene therapy to express secreted recombinant plasma proteins. Here we have applied rAAV transduction of skeletal muscle to express wild-type (ɛ3) and a defective receptor-binding mutant (ɛ2) human apoE transgene in apoE-/- mice. In treated animals, apoE mRNA was present in transduced muscles and, although plasma levels of recombinant apoE fell below the detection levels of our ELISA (ie <10 ng/ml), circulating antibodies to human apoE and rAAV were induced. Up to 3 months after a single administration of rAAV/apoE3, a significant reduction in atherosclerotic plaque density in aortas of treated animals was observed (approximately 30%), indicating that low-level rAAV-mediated apoE3 expression from skeletal muscle can retard atherosclerotic progression in this well-defined genetic model.
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页码：21 / 29
页数：8
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