Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy

Coronary artery disease represents the leading cause of mortality in the developed world. Percutaneous coronary intervention (PCI) 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 to other known AAV serotypes, AAV2.5 demonstrated the highest transduction efficiency of human coronary artery vascular smooth muscle cells (VSMC) 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 Ca(2+ )ATPase (SERCA2a) human gene, known to inhibit VSMC proliferation. At 30 days, human SERCA2a mRNA was detected in transduced arteries. Morphometric analysis revealed a significant decrease of neointimal hyperplasia in AAV2.5-SERCA2a transduced arteries: 28.36±11.30 (n=8) vs 77.96±24.60 (n=10) μm(2), in AAV2.5-GFP-infected, p<0.05. In conclusion, AAV2.5 vector can be considered as a promising safe and effective vector for vascular gene therapy.