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Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis

Gene Therapy volume 24, pages 717–726 (2017)Cite this article

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Abstract

In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and site-specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative activity and anti-restenotic efficacy of stent-immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty.

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Acknowledgements

This work was supported in part by research grants from the National Heart, Lung and Blood Institute including R56-HL 72108, R01HL137762, R01-HL111118, R21- HL131016. Support was also provided by the William J Rashkind Endowment and Erin's Fund of the Children's Hospital of Philadelphia. PTA catheters were kindly provided by NuMed (Hopkinton, NY, USA). Authors wish to acknowledge Ms. Susan Kerns for preparing the manuscript materials for publication.

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Authors and Affiliations

  1. The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    I Fishbein, D T Guerrero, I S Alferiev, J B Foster, N G Minutolo, M Chorny, A M Monteys & R J Levy

  2. The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    I Fishbein, I S Alferiev, N G Minutolo, M Chorny, K H Driesbaugh, C Nagaswami & R J Levy

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Correspondence to I Fishbein.

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Fishbein, I., Guerrero, D., Alferiev, I. et al. Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis. Gene Ther 24, 717–726 (2017). https://doi.org/10.1038/gt.2017.82

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