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Human Molecular Genetics, 2000, Vol. 9, No. 17 2545-2551
© 2000 Oxford University Press

Intramuscular injection of a plasmid vector expressing human apolipoprotein E limits progression of xanthoma and aortic atheroma in apoE-deficient mice

Takis Athanasopoulos1, James S. Owen2, David Hassall3, Matthew G. Dunckley1,+, Jeffrey Drew1,§, Joanne Goodman3, Aristedes D. Tagalakis1,2, David R. Riddell2 and George Dickson,1

1Division of Biochemistry, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK, 2Department of Medicine, Royal Free and University College Medical School, University College London, Royal Free Campus, London NW3 2PF, UK and 3GlaxoWellcome, Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK

Apolipoprotein-E (apoE) protects against coronary artery disease via hepatic removal of atherogenic remnant lipoproteins, sequestration of cholesterol from vessel walls and local anti-oxidant, anti-platelet and anti-inflammatory actions. ApoE gene transfer may thus ameliorate a hyperlipidaemic profile and have beneficial effects at lesion sites to prevent or regress atherosclerosis, a concept endorsed by adenoviral-mediated hepatic expression studies. Here, using plasmid vectors expressing allelic human apoE2 or apoE3 isoforms, skeletal muscle was evaluated as an effective secretory platform for apoE gene augmentation. Transfected myoblasts and myotubes were found to efficiently secrete recombinant apoE in vitro as spherical 10–16 nm lipoprotein particles with pre-ß mobility. Intramuscular plasmid injection in apoE–/– mice, which develop spontaneous atherosclerotic plaque and xanthoma resulted in expression and secretion of apoE. Human apoE mRNA was detected by RT–PCR in injected muscles and, although concentrations of apoE3, which is rapidly cleared from plasma, were near ELISA detection limits, levels of plasma apoE2 were measurable (17.5 ± 4.3 ng/ml). To assess whether muscle-based expression of apoE2 could inhibit atherogenesis, long-term follow-up studies were conducted. Although hyperlipidaemia was not reduced in treated animals, end-point pathology showed clear retardation of atherosclerotic and xanthomatous lesions. Up to 9 months following a single apoE2 plasmid administration, atherosclerotic lesion coverage in proximal aorta was significantly reduced by 20–30% (P < 0.01), whereas development of gross dorsal xanthoma (>5 mm diameter) was effectively reduced to zero. We conclude that expression of apoE from ectopic muscle sites has therapeutic potential to limit progression of atherosclerosis.

+ Present address: Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK

§ Present address: Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, UK To whom correspondence should be addressed. Tel: +44 1784 443545; Fax: +44 1784 434326; Email: g.dickson@rhbnc.ac.uk


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