Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E.
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 (epsilon3) and a defective receptor-binding mutant (epsilon2) 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.
Harris
J D
JD
Centre for Biomedical Research, School of Biological Sciences, Royal Holloway, University of London, Egham, UK.
Schepelmann
S
S
Athanasopoulos
T
T
Graham
I R
IR
Stannard
A K
AK
Mohri
Z
Z
Hill
V
V
Hassall
D G
DG
Owen
J S
JS
Dickson
G
G
D000818:Animals; D000906:Antibodies / Q000097:blood; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy*; D015153:Blotting, Western / Q000379:methods; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
D000906:Antibodies; D001057:Apolipoproteins E