Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E
| Autor: | Zahra Mohri, Julian D. Harris, Silke Schepelmann, David G. Hassall, Ian R. Graham, A.K. Stannard, George Dickson, Hill, James S. Owen, Takis Athanasopoulos |
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| Rok vydání: | 2002 |
| Předmět: |
Apolipoprotein E
Arteriosclerosis Ratón viruses Genetic enhancement Blotting Western Genetic Vectors Enzyme-Linked Immunosorbent Assay Biology medicine.disease_cause Antibodies Virus Viral vector Mice Transduction (genetics) Apolipoproteins E Transduction Genetic Genetics medicine Animals Humans Transgenes Molecular Biology Adeno-associated virus Aorta Mice Knockout Genetic Therapy Dependovirus Virology Molecular biology Adenoviridae Molecular Medicine lipids (amino acids peptides and proteins) |
| Zdroj: | Gene Therapy. 9:21-29 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | 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 (ie10 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. |
| Databáze: | OpenAIRE |
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