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

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 relativ ely short-duration protocols currently employed have encountered significan t hemorrhagic complications, as well as complications from rebound thrombos is. Gene therapy offers a method of local high-level tPA expression over a prolonged time period to avoid both systemic hemorrhage and local rebound t hrombosis. To examine the impact of local tPA overexpression, an adenoviral vector expressing tPA was created. The construct was characterized functio nally in vitro, and the function of the vector was confirmed in vivo by del ivery to the rabbit common femoral artery. Systemic coagulation parameters were not perturbed at any of the doses examined. The impact of local overex pression of tPA on in vivo thrombus formation was examined subsequently in a stasis/injury model of arterial thrombosis. The construct effectively pre vented arterial thrombosis in treated animals, whereas viral and nonviral c ontrols typically developed occluding thrombi. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber ar tery.