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

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

Research output: Contribution to journalArticle

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 potentially 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 functionally characterized in vitro, and the function of the vector was confirmed by in vivo 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 subsequently examined in a stasis/injury model of arterial thrombosis. The construct effectively prevented arterial thrombosis formation in treated animals, while viral and nonviral controls typically developed occluding thrombi (P<0.01 relative to viral and nonviral controls. Across all sections, buffer treated animals averaged 66.5% (+/-13.7%) cross sectional thrombus, while viral controls rose to 78.2% (+/-7.1%). Vessels treated with the adenoviral-tPA construct, in contrast, averaged 19.3% (+/-3.2%). These results remained after three days, during which most rebound thrombosis would have occurred. Thus a locally thromboresistant small caliber artery with minimal risk of systemic hemorrhagic complications can be produced using this construct.

Original languageEnglish
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998
Externally publishedYes

Fingerprint

t-plasminogen activator
Gene therapy
plasminogen activator
gene therapy
Plasminogen Activators
thrombosis
Tissue Plasminogen Activator
Genetic Therapy
Thrombosis
rabbits
Rabbits
Animals
arteries
Coagulation
myocardial infarction
thighs
coagulation
Buffers
Femoral Artery
Standard of Care

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

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

In: FASEB Journal, Vol. 12, No. 5, 20.03.1998.

Research output: Contribution to journalArticle

Weinfeld, A, Waugh, JM, Kattash, M, Li, J, Yuksel, E, Lussier, E, Saxena, R, Thung, SN, Woo, SLC & Shenaq, SM 1998, 'Gene therapy to promote thromboresistance: Local over-expression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model', FASEB Journal, vol. 12, no. 5.
Weinfeld, A. ; Waugh, J. M. ; Kattash, M. ; Li, J. ; Yuksel, E. ; Lussier, E. ; Saxena, Romil ; Thung, S. N. ; Woo, S. L C ; Shenaq, S. M. / Gene therapy to promote thromboresistance : Local over-expression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. In: FASEB Journal. 1998 ; Vol. 12, No. 5.
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AU - Lussier, E.

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