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Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model

Gene Therapy volume 17, pages 1279–1287 (2010)Cite this article

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Abstract

Both atherosclerosis and arterial interventions induce oxidative stress mediated in part by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that have a pivotal role in the development of neointimal hyperplasia and restenosis. For small interfering RNA (siRNA) targeting of the NOX2 (Cybb) component of the NADPH oxidase to prevent restenosis, gene transfer with viral vectors is effective, but raises safety issues in humans. We developed a new approach using the amino-acid-based nanoparticle HB-OLD7 for local delivery of siRNA targeting NOX2 to the arterial wall. siRNA–nanoparticle complexes were transferred into the regional carotid artery walls after angioplasty in an atherosclerotic rat model. Compared with angioplasty controls, Cybb gene expression (measured by quantitative reverse transcriptase-PCR) in the experimental arterial wall 2 weeks after siRNA was reduced by >87%. The neointima-to-media-area ratio was decreased by >83%, and the lumen-to-whole-artery area ratio was increased by >89%. Vital organs showed no abnormalities and splenic Cybb gene expression showed no detectable change. Thus, local arterial wall gene transfer with HB-OLD7 nanoparticles provides an effective, nonviral system for efficient and safe local gene transfer in a clinically applicable approach to knock down an NADPH oxidase gene. Local arterial knockdown of the Cybb gene significantly inhibited neointimal hyperplasia and preserved the vessel lumen without systemic toxicity.

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Acknowledgements

We thank Tariq M Rana, PhD and Huricha Baigude, PhD, Burnham Institute for Medical Research, La Jolla, CA, for providing nanoparticles and for helpful study discussions; Stephen Baker, MScPH, Senior Biostatistician, Department of Cell Biology and Information Resources for assistance of statistical analysis; Paul S Furcinitti, PhD, Director of Digital Light Microscopy Core Facility for confocal microscopy and image analysis, and Jeffrey Nickerson, PhD, Department of Cell Biology, Director of Confocal Microscopy Core Facility, the University of Massachusetts Medical School. This study was supported by the Bugher Foundation (to JML), NIH grant numbers R21AI079788 and R01DK54369 (to PEN), R21EB007767 (to MJG), R01HL075353 (to LMM) and University of Massachusetts Medical School Chair Research Fund (to LMM).

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Authors and Affiliations

  1. Division of Vascular Surgery, Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    J M Li, P Dargon & L M Messina

  2. Departments of Pediatrics and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    P E Newburger & X Zhang

  3. Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, MA, USA

    M J Gounis

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  1. J M Li
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Correspondence to J M Li.

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Li, J., Newburger, P., Gounis, M. et al. Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model. Gene Ther 17, 1279–1287 (2010). https://doi.org/10.1038/gt.2010.69

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