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.

引用

页码：21 / 29

页数：8

共 107 条

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