Bioreducible polymer-mediated gene therapy for the treatment of ischemic heart disease

Coronary heart disease, especially myocardial infarction, is a serious and deadly disease that remains the number one cause of death in developed nations. While physicians have a wide array of drugs and tools at their disposal to treat myocardial infarction, there is a scarcity of drugs that effectively prevent the pathological remodeling of the left ventricle that occurs after acute infarction and greatly predisposes the patient to the risk of heart failure. This dissertation focuses on identifying nonviral, bioreducible polymer-based gene therapies to limit infarct expansion, prevent left ventricular remodeling, and retain heart function after myocardial infarction. Bioreducible polymers represent a major advancement in nonviral technology to transfect primary cells, with high efficiency, and low cytotoxicity. We first examined a combined gene/cell therapy-based strategy by implanting VEGF165-transfected primary skeletal myoblasts to the myocardium of infarcted rat hearts. The VEGF-expressing skeletal myoblasts acted as bioreactors, secreting proangiogenic VEGF and inducing new vessel formation in the infarcted hearts. This treatment strategy produced both global and regional improvements in the left ventricle, improving ejection fraction, decreasing cell death, and limiting left ventricular remodeling. A cationic polymer system utilizing arginine-grafted bioreducible polymer (ABP) was also used to efficiently mediate siRNA knockdown of BNIP3, a hypoxia-inducible iv proapoptotic protein. siRNA-mediated BNIP3 knockdown both in vitro and in vivo protected rat primary cardiomyocytes from hypoxic death. The inhibition of BNIP3 in acutely ischemic rat hearts resulted in improved retention of ejection fraction, decreased infarct formation, decreased cellular remodeling, and decreased left ventricular remodeling.