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

Abstract

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.

• Authors: J D Harris, S Schepelmann, T Athanasopoulos, I R Graham, A K Stannard, Z Mohri, V Hill, D G Hassall, J S Owen, G Dickson
• Journal: Gene therapy (Gene Ther) Vol. 9 Issue 1 Pg. 21-9 (Jan 2002) ISSN: 0969-7128 [Print] England
• PMID: 11850719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Apolipoproteins E

Topics

• Animals
• Antibodies (blood)
• Aorta (pathology)
• Apolipoproteins E (analysis, genetics, immunology)
• Arteriosclerosis (pathology, therapy)
• Blotting, Western (methods)
• Dependovirus (genetics)
• Enzyme-Linked Immunosorbent Assay (methods)
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• Humans
• Mice
• Mice, Knockout
• Transduction, Genetic (methods)
• Transgenes