Myocardial Gene Transfer of Vascular Endothelial Growth Factor for Therapeutic Angiogenesis in Patients with Myocardial Ischemia

Erwin Schrödinger Fellowship J 1935 Local Gene Transfer of Vascular Endothelial Growth Factor Manfred CEJNA 08.05.2000 The study is a gene therapy protocol that will evaluate the safety and bioactivity of directly administering a plasmid containing the cDNA for vascular endothelial growth factor (phVEGF165) to the myocardium of patients with myocardial ischemia. A total of 30 adult men and women will participate in this dose-escalating study. Subjects will be eligible if they have stable exertional. angina pectoris due to angiographically documented coronary artery disease with areas of viable but underperfused myocardium and have been judged not to be optimal candidates for conventional therapy (drugs, PTA/stent or CAEG surgery). The strategy is designed to stimulate the growth of collateral vessels around the occluded arterial segments and thereby improve perfusion to the myocardium. The clinical response will be evaluated by serial studies performed before and after gene transfer, including exercise treadmill testing, dobutamine stress SPECT-sestamibi myocardial perfusion, and coronary angiography. In one arm of the study, direct intramyocardiall gene transfer will be performed through a "mini" left anterior thoracotomy to deliver a solution of phVEGF165 to the myocardium. The transgene will be delivered as naked DNA; no adjunctive agents, including liposomes or viral vectors, will be employed. Total doses of 125,250, and 500 m g respectively will be administered to 10 patients each. Each patient will receive 4 injections, each in a volume of 2.0 ml. After completing the injections, the pericardium will be left partially open, and the thoracotomy incision closed. A chest tube in the left pleural space will be required for about 24 hours. The patient can be extubated in the operating room and postoperatively will be monitored according to the protocol used for minimally invasive coronary bypass surgery. In the other arm of the study, myocardial gene transfer will be performed via a percutaneous catheter delivery system to deliver a solution of phVEGF165 to the myocardium; this will also be a dose-escalating study in which total doses of 125, 250, and 500 pg respectively will be administered to 10 patients each and each patient will receive 6 injections; each of the 6 injections will deliver a total of total of 1.0 ml saline. The plasmid into which the VEGF cDNA has been inserted (phVEGF165) is a simple eucaryotic expression plasmid that utilizes the 763-base-pair cytomegallovirus (CNM promoter/enhancer to drive VEGF expression. The plasmid DNA will be prepared at the time of gene transfer in St. Elizabeth`s Medical Center`s Human Gene Therapy Laboratory; DNA will be prepared from cultures of phVEGF165-transformed E. coli by the Qiagen method. Plasmid will be reconstituted in reconstituted in sterile saline at room temperature in preparation for use.