Clinical trials of myocardial VEGF gene transfer

Abstract

Preclinical studies have documented that gene transfer of plasmid DNA encoding for secreted angiogenic cytokines such as vascular endothelial growth factor (VEGF) can induce therapeutic angiogenesis in animal models. Based on these studies, we have conducted 4 Phase I clinical trials of direct intramyocardial injection of VEGF plasmid DNA in patients with otherwise inoperable myocardial ischemia. In the first 2 trials, VEGF-1 (30 patients) or VEGF-2 (30 patients) plasmid DNA was administered through a mini-thoracotomy incision in an open label nonrandomized fashion as sole therapy. The majority of patients in both study groups experienced a significant reduction in angina frequency and improvement in Canadian Cardiovascular Society (CCS) angina class associated with objective evidence of improved myocardial perfusion documented by myocardial perfusion imaging and left ventricular electromechanical mapping. The subsequent development of a catheter-based approach to myocardial gene transfer has allowed us to conduct 2 randomized blinded trials of VEGF-2 gene transfer in a total of 25 patients. While a placebo effect was evident early post-treatment, VEGF-treated patients demonstrated significantly better results in terms of improvement in angina class and objective evidence of improvement in myocardial perfusion. These early Phase I trials confirm that direct myocardial gene transfer with VEGF is safe (overall 1 year mortality 3.5%) and should thus permit larger scale, appropriately randomized trials to be performed in order to more definitively evaluate its therapeutic efficacy.