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- Title
Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy.
- Authors
Lompré, A-M; Hadri, L; Merlet, E; Keuylian, Z; Mougenot, N; Karakikes, I; Chen, J; Atassi, F; Marchand, A; Blaise, R; Limon, I; McPhee, S W J; Samulski, R J; Hajjar, R J; Lipskaia, L
- Abstract
Coronary artery disease represents the leading cause of mortality in the developed world. Percutaneous coronary intervention involving stent placement remains disadvantaged by restenosis or thrombosis. Vascular gene therapy-based methods may be approached, but lack a vascular gene delivery vector. We report a safe and efficient long-term transduction of rat carotid vessels after balloon injury intervention with a translational optimized AAV2.5 vector. Compared with other known adeno-associated virus (AAV) serotypes, AAV2.5 demonstrated the highest transduction efficiency of human coronary artery vascular smooth muscle cells (VSMCs) in vitro. Local delivery of AAV2.5-driven transgenes in injured carotid arteries resulted in transduction as soon as day 2 after surgery and persisted for at least 30 days. In contrast to adenovirus 5 vector, inflammation was not detected in AAV2.5-transduced vessels. The functional effects of AAV2.5-mediated gene transfer on neointimal thickening were assessed using the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) human gene, known to inhibit VSMC proliferation. At 30 days, human SERCA2a messenger RNA was detected in transduced arteries. Morphometric analysis revealed a significant decrease in neointimal hyperplasia in AAV2.5-SERCA2a-transduced arteries: 28.36±11.30 (n=8) vs 77.96±24.60 (n=10) μm2, in AAV2.5-green fluorescent protein-infected, P<0.05. In conclusion, AAV2.5 vector can be considered as a promising safe and effective vector for vascular gene therapy.
- Subjects
CELLULAR signal transduction; MUSCLE cells; VASCULAR smooth muscle; CORONARY restenosis; GENE therapy; ADENO-associated virus; TRANSGENES
- Publication
Gene Therapy, 2013, Vol 20, Issue 9, p901
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2013.13