The long-range goal of our research program is the development of more effective and safer gene-based therapies for a variety of diseases. The major focus of this study is the use of electrically mediated non-viral gene delivery for the induction of angiogenesis as a potential treatment of coronary artery disease and ischemic myocardial disease (CAD). The project is divided into two parts. A R21 feasibility study will be performed initially to determine if utilizing electroporation to deliver plasmids containing angiogenic factors to cardiac muscle can be successfully accomplished and to determine the electroporation characteristics and plasmid concentrations to identify a successful protocol. These steps are necessary to move forward to establish a therapeutic protocol. This portion of the study has three specific aims as follows: 1. to establish electroporation delivery parameters to obtain optimal expression following plasmid DNA delivery to cardiac muscle (CAD);2. to develop a prototype catheter based electroporation delivery system and to determine the time that expression levels can be maintained;and 3. to determine if electroporation delivery of a plasmid encoding for VEGF can induce angiogenesis in the heart.. Successful completion of this portion of the project will establish delivery criteria to cardiac muscle. The results should demonstrate that the procedure can be performed safely and effectively. The second part of this project is a R33 developmental phase. This portion of the project will expand and extend the initial studies. Work will be focused on evaluating the potential of electroporation mediated gene therapy for treatment of coronary artery disease. The work will culminate in testing this approach in an appropriate ischemic model.
The Specific Aims to be accomplished in this phase of the study are as follows: 1. to develop appropriate electrode systems, both catheter-based and for open chest procedures;2. to evaluate gene delivery for CAD with respect to long-term effects and vessel development;and 3. to evaluate the delivery protocol in an appropriate disease model. The electroporation delivery characteristics and protocols are anticipated to be successful based on the work of this group in other organs and tissues. The described protocol is a major advancement of proven techniques to a new species model and a new pathologic state. By including an experienced cardiovascular surgeon and renowned clinical cardiac electrophysiologist, this inter-disciplinary team is extraordinarily capable of moving into a new area of investigation utilizing and expanding current techniques and technology to plan and implement this unique, novel, and innovative protocol with high likelihood of success. This will result in an innovative method for delivery of plasmids encoding for angiogenic factors to the heart for the treatment of chronic vascular disease. Public Health Relevance: Coronary artery disease is a growing health problem in the United States and the world. The development of new or improvement of existing therapeutic approaches is critical to reducing the morbidity and mortality of this disease. Development of a non-viral gene delivery system for factors that will facilitate revascularization of ischemic tissue would be an important advance. The work proposed in this study will evaluate electroporation as a means to deliver plasmids encoding angiogenic factors directly to ischemic tissue as a potential therapy.
|Bulysheva, A A; Hargrave, B; Burcus, N et al. (2016) Vascular endothelial growth factor-A gene electrotransfer promotes angiogenesis in a porcine model of cardiac ischemia. Gene Ther 23:649-56|
|Hargrave, B; Downey, H; Strange Jr, R et al. (2013) Electroporation-mediated gene transfer directly to the swine heart. Gene Ther 20:151-7|
|Marshall Jr, W G; Boone, B A; Burgos, J D et al. (2010) Electroporation-mediated delivery of a naked DNA plasmid expressing VEGF to the porcine heart enhances protein expression. Gene Ther 17:419-23|