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Article Dans Une Revue Gene Therapy Année : 2013

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

A-M Lompre
  • Fonction : Auteur
L. Hadri
  • Fonction : Auteur
E. Merlet
  • Fonction : Auteur
Z. Keuylian
  • Fonction : Auteur
N. Mougenot
  • Fonction : Auteur
I. Karakikes
  • Fonction : Auteur
Jie Chen
  • Fonction : Auteur
  • PersonId : 761941
  • IdRef : 200253832
F. Atassi
  • Fonction : Auteur
A. Marchand
  • Fonction : Auteur
S. W. J. Mcphee
  • Fonction : Auteur
R. J. Samulski
  • Fonction : Auteur
R. J. Hajjar
  • Fonction : Auteur
L. Lipskaia
  • Fonction : Auteur

Résumé

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) mu m(2), 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.

Dates et versions

hal-01545430 , version 1 (22-06-2017)

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Citer

A-M Lompre, L. Hadri, E. Merlet, Z. Keuylian, N. Mougenot, et al.. Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy. Gene Therapy, 2013, 20 (9), pp.901-912. ⟨10.1038/gt.2013.13⟩. ⟨hal-01545430⟩
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