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

Gene Therapy volume 9, pages 21–29 (2002)Cite this article

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 (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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Acknowledgements

Parts of this work were supported by grants from the British Heart Foundation, Sir Jules Thorn Charitable Trust, European Union and Wellcome Trust. We gratefully thank J Kleinschmidt and D Grimm for providing the pDG plasmid and JL Breslow for providing the human apoE2 and apoE3 cDNAs. We thank A Tagalakis for providing the partially-purified recombinant apoE.

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Authors and Affiliations

  1. Centre for Biomedical Research, School of Biological Sciences, Royal Holloway, University of London, Egham, UK

    JD Harris, T Athanasopoulos, IR Graham, V Hill & G Dickson

  2. Department of Medicine, Centre of Hepatology, Royal Free and University College Medical School, London, UK

    S Schepelmann, AK Stannard, Z Mohri & JS Owen

  3. GlaxoSmithKline, Medicines Research Centre, Stevenage, UK

    DG Hassall

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Harris, J., Schepelmann, S., Athanasopoulos, T. et al. Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E. Gene Ther 9, 21–29 (2002). https://doi.org/10.1038/sj.gt.3301615

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  • DOI: https://doi.org/10.1038/sj.gt.3301615

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