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Gene-eluting stents: non-viral, liposome-based gene delivery of eNOS to the blood vessel wall in vivo results in enhanced endothelialization but does not reduce restenosis in a hypercholesterolemic model

Gene Therapy volume 19, pages 321–328 (2012)Cite this article

Abstract

Although successful, drug-eluting stents require significant periods of dual anti-platelet therapy with a persistent risk of late stent thrombosis due to inhibition of re-endothelialization. Endothelial regeneration is desirable to protect against in-stent thrombosis. Gene-eluting stents may be an alternative allowing inhibition of neointima and regenerating endothelium. We have shown that adenoviral endothelial nitric oxide synthase (eNOS) delivery can result in significantly decreased neointimal formation and enhanced re-endothelialization. Here, we examined non-viral reporter and therapeutic gene delivery from a stent. We coated lipoplexes directly onto the surface of stents. These lipostents were then deployed in the injured external iliac artery of either normal or hypercholesterolemic New Zealand White rabbits and recovered after 28 days. Lipoplexes composed of lipofectin and a reporter lacZ gene or therapeutic eNOS gene were used. We demonstrated efficient gene delivery at 28 days post-deployment in the media (21.3±7.5%) and neointima (26.8±11.2%). Liposomal delivery resulted in expression in macrophages between the stent struts. This resulted in improved re-endothelialization as detected by two independent measures compared with vector and stent controls (P<0.05 for both). However, in contrast to viral delivery of eNOS, liposomal eNOS does not reduce restenosis rates. The differing cell populations targeted by lipoplexes compared with adenoviral vectors may explain their ability to enhance re-endothelialization without affecting restenosis. Liposome-mediated gene delivery can result in prolonged and localized transgene expression in the blood vessel wall in vivo. Furthermore, lipoeNOS delivery to the blood vessel wall results in accelerated re-endothelialization; however, it does not reduce neointimal formation.

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Acknowledgements

This work is funded by an Enterprise Ireland Grant (CFTD 105-07). TOB is also funded by a CSET Grant to REMEDI from Science Foundation Ireland. KMC has received funding from the Health Research Board Ireland. We wish to acknowledge the help of Dr Ailish Hynes, Department of Physiology, NUI Galway, in the preparation of this manuscript.

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Author notes

  1. F Sharif, S O Hynes and K J A McCullagh: These authors contributed equally to this work.

Authors and Affiliations

  1. Regenerative Medicine Institute, National University of Ireland, Galway, Ireland

    F Sharif, S O Hynes, K J A McCullagh, S Ganley, U Greiser, P McHugh, F Barry & T O'Brien

  2. Department of Cardiology, University College Hospital, Galway, Ireland

    F Sharif & J Crowley

  3. Department of Medicine, Clinical Sciences Institute, University College Hospital, Galway, Ireland

    S O Hynes & T O'Brien

  4. Department of Physiology, National University of Ireland, Galway, Ireland

    K J A McCullagh

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  1. F Sharif
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Correspondence to T O'Brien.

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Sharif, F., Hynes, S., McCullagh, K. et al. Gene-eluting stents: non-viral, liposome-based gene delivery of eNOS to the blood vessel wall in vivo results in enhanced endothelialization but does not reduce restenosis in a hypercholesterolemic model. Gene Ther 19, 321–328 (2012). https://doi.org/10.1038/gt.2011.92

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