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

Gene Therapy volume 20, pages 901–912 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by AHA SDG 0930116N (LL), by NIH 1K01HL103176 (LH), by Leducq Foundation through the Caerus network (05 CVD 03 to AML and RJH), by NIH R01 HL078691, HL057263, HL071763, HL080498 and HL083156 (RJH).

Author contributions

A-ML, SWJMP, LL and RJH contributed to the conception, design, analysis and interpretation of all data; drafting the manuscript, revising it critically for important intellectual content and final approval of the manuscript. RJS and SWJMP designed and produced virus vectors. NM, A-ML, LL, EM, ZK and JC performed the in vivo gene transfer. A-ML, LL, EM and FA performed immunohistochemistry and morphometry experiments and the analysis of results. LL, EM and AM performed the in vitro data. LL, IK, RB and IL contributed the quantitative reverse transcription-PCR analysis. LH led the fluorescence-activated cell sorting analysis.

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Authors and Affiliations

  1. INSERM, UMRS 956, Paris, France

    A-M Lompré, E Merlet, F Atassi, A Marchand & L Lipskaia

  2. UPMC-Paris 6, Paris, France

    A-M Lompré, E Merlet, F Atassi, A Marchand & L Lipskaia

  3. Mount Sinai School of Medicine, Cardiovascular Research Center, New York, NY, USA

    L Hadri, I Karakikes, J Chen, R J Hajjar & L Lipskaia

  4. Université Paris 6, UR4, Paris, France

    Z Keuylian, R Blaise & I Limon

  5. Université Paris 6, PECMV IFR 14, Paris, France

    N Mougenot

  6. Asklepios BioPharmaceutical Inc., Chapel Hill, NC, USA

    S W J McPhee

  7. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    R J Samulski

  8. Transatlantic Cardiovascular Research Center: INSERM/UPMC/Mount Sinai School of Medicine, Paris/New York

    A-M Lompré, L Hadri, E Merlet, Z Keuylian, I Karakikes, J Chen, F Atassi, A Marchand, I Limon, R J Hajjar & L Lipskaia

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  1. A-M Lompré
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Correspondence to L Lipskaia.

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Lompré, AM., Hadri, L., Merlet, E. 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 Ther 20, 901–912 (2013). https://doi.org/10.1038/gt.2013.13

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