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Prevention of restenosis by a herpes simplex virus mutant capable of controlled long-term expression in vascular tissue in vivo

Gene Therapy volume 8, pages 1840–1846 (2001)Cite this article

Abstract

Neointimal hyperplasia resulting from vascular smooth muscle cell (SMC) proliferation and luminal migration is the major cause of autologous vein graft failure following vascular coronary or peripheral bypass surgery. Strategies to attenuate SMC proliferation by the delivery of oligonucleotides or genes controlling cell division rely on the use of high concentrations of vectors, and require pre-emptive disruption of the endothelial cell layer. We report a genetically engineered herpes simplex virus (HSV-1) mutant that, in an in vivo rabbit model system, infects all vascular layers without prior injury to the endothelium; expresses a reporter gene driven by a viral promoter with high efficiency for at least 4 weeks; exhibits no systemic toxicity; can be eliminated at will by administration of the antiviral drug acyclovir; and significantly reduces SMC proliferation and restenosis in vein grafts in immunocompetent hosts.

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Acknowledgements

The authors wish to thank the following for their contribution to this project: Craig Wardrip, DVM (husbandry), Karen Hynes (immunohistochemistry, cell culture), Ann Koons (immunohistochemistry), Gordon Bowie (histology), Mary Cernius (histology). This work is supported by American Heart Association Scientist Development Grant 9930338Z to Lewis Schwartz and RO1 CA71933 to Ralph R Weichselbaum and Bernard Roizman. Christopher L Skelly is supported by Thoracic Surgery Research Fellowship No. 99019, Thoracic Surgery Foundation. Shari L Meyerson is supported by Cardiovascular Pathophysiology and Biochemistry Training Grant, NIH/NHLBI 5T32 HL07237. Michael A Curi is supported in part by a grant from the Coller Society.

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Authors and Affiliations

  1. Department of Surgery, Section of Vascular Surgery, University of Chicago, Chicago, IL, USA

    CL Skelly, MA Curi, SL Meyerson, DH Woo, D Hari, JE Vosicky & LB Schwartz

  2. Marjorie B Kovler Viral Oncology Laboratories, University of Chicago, Chicago, IL, USA

    SJ Advani & B Roizman

  3. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA

    D Hari, SJ Advani, HJ Mauceri & RR Weichselbaum

  4. Department of Pathology, University of Chicago, Chicago, IL, USA

    S Glagov

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  1. CL Skelly
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  2. MA Curi
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  3. SL Meyerson
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Skelly, C., Curi, M., Meyerson, S. et al. Prevention of restenosis by a herpes simplex virus mutant capable of controlled long-term expression in vascular tissue in vivo. Gene Ther 8, 1840–1846 (2001). https://doi.org/10.1038/sj.gt.3301597

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  • DOI: https://doi.org/10.1038/sj.gt.3301597

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