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Chapter 8: CARDIOVASCULAR TISSUE MODIFICATION BY GENETIC APPROACHES CLINICAL TRIALS

Clinical trials in cardiovascular gene therapy have gone forward in two areas: vascular proliferative diseases and angiogenesis. The results of a Phase I/II randomized study of a cell cycle inhibitor have been reported recently.89 In this study, cell cycle blockade by ex vivo gene therapy of experimental vein grafts was accomplished with a dominant negative transcription decoy, E2F, that leads to G1 arrest and inhibition of cell proliferation. The investigators hypothesized that this transcription decoy would inhibit the neointimal hyperplasia and subsequent accelerated atherosclerosis that lead to human bypass graft failure. This hypothesis was tested in a prospective, randomized, controlled trial to investigate the safety and biologic efficacy of intraoperative gene therapy in patients receiving bypass vein grafts. Patients undergoing infrainguinal bypass grafting were randomized to decoy oligodeoxynucleotide (which binds and inactivates E2F), scrambled oligodeoxynucleotides, or no treatment. Oligonucleotide was delivered to grafts intraoperatively by ex vivo pressure-mediated transfection. Since this was a Phase I/II study, the primary end points were safety and inhibition of target cell cycle regulatory genes and of DNA synthesis in the grafts. The investigators found that the E2F decoy treatment reduced proliferating-cell nuclear antigen and c-myc mRNA concentrations as well as cell proliferation indices. Twelve months later, there were fewer clinical complications in the E2F treatment group, defined as fewer graft occlusions, revisions, or severe lesions. The investigators concluded that the intraoperative transfection of human bypass vein grafts with E2F decoy oligodeoxynucleotide was not only safe and feasible but also achieved inhibition of cell cycle genes and cell replication.89

Several protocols have now been initiated to promote angiogenesis for myocardial and peripheral ischemia. These studies have administered recombinant protein, plasmid DNA, or adenoviral vectors encoding bFGF, VEGF, aFGF, or FGF-4 by direct injection into the heart or limb muscle or by direct intracoronary infusion. Thus different genes, vectors, routes of delivery, and tissues are being examined. These studies to date have been Phase I (i.e., safety and toxicity) studies in which clinical efficacy is not an end point due to the small number of patients. Some of these Phase I protocols have been completed and reported. In a study to treat myocardial ischemia, recombinant aFGF was injected directly into the anatomosis site of the left internal mammary artery (LIMA) and into the left anterior descending artery (LAD) of patients undergoing coronary bypass surgery.90 Patients with peripheral ischemia have been treated with direct injections of plasmid DNA encoding VEGF.94 These Phase I studies are promising. The treatments to date have been safe, with no substantial toxicities. Progression to Phase II/III studies in which dose escalation, double-blind randomization, and measurements of clinical efficacy are performed is warranted.

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