Gene therapy to promote thromboresistance: Local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model

J. M. Waugh, M. Kattash, J. Li, E. Yuksel, M. D. Kuo, M. Lussier, A. B. Weinfeld, Romil Saxena, E. D. Rabinovsky, S. Thung, S. L C Woo, S. M. Shenaq

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Tissue-type plasminogen activator (tPA) catalyzes the rate-limiting initial step in the fibrinolytic cascade. Systemic infusion of tPA has become the standard of care for acute myocardial infarction. However, even the relatively short-duration protocols currently employed have encountered significant hemorrhagic complications, as well as complications from rebound thrombosis. Gene therapy offers a method of local high-level tPA expression over a prolonged time period to avoid both systemic hemorrhage and local rebound thrombosis. To examine the impact of local tPA overexpression, an adenoviral vector expressing tPA was created. The construct was characterized functionally in vitro, and the function of the vector was confirmed in vivo by delivery to the rabbit common femoral artery. Systemic coagulation parameters were not perturbed at any of the doses examined. The impact of local overexpression of tPA on in vivo thrombus formation was examined subsequently in a stasis/injury model of arterial thrombosis. The construct effectively prevented arterial thrombosis in treated animals, whereas vital and nonviral controls typically developed occluding thrombi. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery.

Original languageEnglish (US)
Pages (from-to)1065-1070
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number3
DOIs
StatePublished - Feb 2 1999
Externally publishedYes

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Tissue Plasminogen Activator
Plasminogen Activators
Genetic Therapy
Thrombosis
Rabbits
Femoral Artery
Standard of Care
Arteries
Myocardial Infarction
Hemorrhage
Wounds and Injuries

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Gene therapy to promote thromboresistance : Local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. / Waugh, J. M.; Kattash, M.; Li, J.; Yuksel, E.; Kuo, M. D.; Lussier, M.; Weinfeld, A. B.; Saxena, Romil; Rabinovsky, E. D.; Thung, S.; Woo, S. L C; Shenaq, S. M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 3, 02.02.1999, p. 1065-1070.

Research output: Contribution to journalArticle

Waugh, J. M. ; Kattash, M. ; Li, J. ; Yuksel, E. ; Kuo, M. D. ; Lussier, M. ; Weinfeld, A. B. ; Saxena, Romil ; Rabinovsky, E. D. ; Thung, S. ; Woo, S. L C ; Shenaq, S. M. / Gene therapy to promote thromboresistance : Local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 3. pp. 1065-1070.
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