Gene therapy for ischemic heart disease: therapeutic potential

Abstract

Gene therapy is evolving as an alternative mode to pharmacological intervention in the treatment of cardiovascular diseases. Experimental observations indicating that introduction of genes encoding for angiogenic peptide growth factors could result in improvement in perfusion to ischemic myocardium have led to the initiation of a number of preliminary clinical trials to evaluate this therapeutic modality. Sustained expression of the growth factor product from somatic cells transfected with the DNA for that protein has proven to be one of the major advantages of a gene therapy based approach over administration of the recombinant protein. A number of gene therapy vectors have been developed, prominent among these being adenoviral vectors and naked plasmid DNA. Whereas plasmid DNA results in less efficient transfection, its tolerability profile may be superior to adenoviral vectors. Plasmid DNA is particularly suitable when the gene product to be produced is capable of being secreted by the cell which is producing it. Vascular endothelial growth factor (VEGF) is not only essential to the process of angiogenesis, but, because it can be secreted from intact cells, appears to be ideal for gene transfer therapy aimed at improving perfusion to ischemic myocardium. The DNA can be delivered to the myocardium by intra-arterial or intramuscular injection. At present, direct injection into the muscle either via a small thoracotomy incision or by use of a recently developed percutaneous catheter technique appears to be superior to arterial administration. Several clinical trials based on intramyocardial injection of VEGF DNA in patients with otherwise inoperable coronary artery disease and intractable angina pectoris have recently been completed. These phase I trials have documented the tolerability of gene transfer using plasmid DNA and show promise of being able to improve myocardial perfusion and reduce anginal symptoms in the majority of patients treated thus far. While the trials involving gene transfer via a thoracotomy did not allow for randomization to a placebo group, the recent advent of a percutaneous delivery modality has allowed for randomization which should enhance our ability to determine whether angiogenic gene therapy will prove to be as effective as initial results suggest. In the future, results from such randomized placebo-controlled trials, improvement in vectors utilized for gene transfer and innovative new delivery techniques will undoubtedly enhance the potential of this novel approach to myocardial revascularization.