In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene

Raul J. Guzman, Edward A. Hirschowitz, Steven L. Brody, Ronald Crystal, Stephen E. Epstein, Toren Finkel

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

Restenosis, a process characterized in part by excessive smooth muscle cell (SMC) proliferation in areas of vascular injury, occurs in up to 50% of patients undergoing balloon angioplasty. In an effort to develop a treatment strategy for restenosis, we constructed a replication-deficient recombinant adenovirus (AdMLP.HSTK) containing the herpes simplex virus thymidine kinase gene (HSV tk). This viral gene product phosphorylates the prodrug ganciclovir to form a nucleoside analog that inhibits DNA synthesis. Cultured primary rat SMCs infected with AdMLP.HSTK were completely growth-inhibited by incubation in ganciclovir-containing medium. In addition, when only a portion of the SMC population received the HSV tk transgene, an inhibitory effect on neighboring SMCs was evident. Evaluation of this strategy in vivo using a rat carotid balloon injury model demonstrated that local infection of injured arteries with AdMLP.HSTK followed by 2 weeks of systemic ganciclovir treatment significantly (P < 0.01) reduced injury-induced SMC accumulation. In contrast, there was no suppression of injury-induced SMC accumulation in animals infected with AdMLP.HSTK but not receiving ganciclovir or in those animals infected with a control adenovirus and either treated or not treated with ganciclovir. These results demonstrate the potential utility of adenovirus-mediated gene transfer for treatment of restenosis after balloon injury.

Original languageEnglish
Pages (from-to)10732-10736
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number22
DOIs
Publication statusPublished - 25 Oct 1994
Externally publishedYes

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Ganciclovir
Thymidine Kinase
Simplexvirus
Vascular Smooth Muscle
Adenoviridae
Smooth Muscle Myocytes
Wounds and Injuries
Genes
Balloon Angioplasty
Vascular System Injuries
Prodrugs
Viral Proteins
Transgenes
Nucleosides
Therapeutics
Arteries
Cell Proliferation
DNA
Growth
Infection

Keywords

  • gene therapy
  • restenosis

ASJC Scopus subject areas

  • General

Cite this

In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. / Guzman, Raul J.; Hirschowitz, Edward A.; Brody, Steven L.; Crystal, Ronald; Epstein, Stephen E.; Finkel, Toren.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 22, 25.10.1994, p. 10732-10736.

Research output: Contribution to journalArticle

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