We made significant progress towards our long term goal of applying the techniques of gene transfer to the treatment of cardiovascular disease. The principal disease targets are thrombosis, proliferative arterial disease such as occurs after balloon angioplasty, and pulmonary hypertension. The application of gene transfer to the prevention of thrombosis was pursued in a baboon model of prosthetic graft thrombosis. Endothelial cells that were genetically modified to express high levels of either tissue plasminogen activator or urokinase consistently decreased thrombus deposition in this system. The antithrombotic effect was confined to the vicinity of the graft, with no evidence of systemic fibrinolysis. The concept of local antithrombotic therapy delivered by gene transfer is established by these experiments. Transfer of plasminogen activator genes alone or in combination with other genes provides a powerful and specific approach to local antithrombotic therapy. Efforts to develop a gene therapy approach for proliferative arterial disease were focused on optimization of adenovirus-mediated gene transfer into injured arteries. The ultimate goal of these experiments is to both understand and manipulate the proliferative response to arterial injury. Quantitative biochemical and histologic analyses revealed the existence of a narrow window of virus concentration in which high levels of gene transfer and expression were detected in the absence of associated tissue toxicity. This potentially therapeutic window is now being exploited in experiments in which genes with biological activity are introduced into injured arteries. In the pulmonary gene transfer project, adenoviral vectors were used to achieve expression of a marker gene within the pulmonary vasculature and lung parenchyma of rats.
