Research Project
9202066
ABSTRACT Novel Stem Cell Therapy for Acute Myocardial Infarction in Diabetes Mellitus Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide leading to over 17.3 million deaths per year. Over 700,000 heart attacks occur in the U.S. each year, which cause about 120,000 deaths. After acute myocardial infarction (AMI), ischemic tissues undergo cell death from necrosis and apoptosis, followed by inflammation and a process of granulation leading to scar tissue formation. Due to the poor regenerative ability of cardiomyocytes, improved therapies are sorely needed to both protect and restore ischemic tissues immediately post-AMI. Patients with type 2 diabetes mellitus (T2DM) have a higher incidence of CVD and worse prognosis than those without diabetes (Williams, 2003): approximately two-thirds of diabetic-associated deaths are due to heart disease or stroke (Fox, 2007; Dailey, 2014; Intl Diabetes Federation, 2011) and those with AMI have higher rates of re-occlusion and both 30 day and 1 year mortality (Williams, 2003). Moreover, women diagnosed with diabetes after age 25 have a significantly greater risk of CVD mortality and hospitalization than men (Roche, 2013). Overwhelming evidence supports a direct link between diabetic vascular complications and endothelial dysfunction (Jarajapu, 2010). The inability to repair damaged vasculature is due in large part not only to a reduction in the number of circulating endothelial progenitor cells (EPC), but by their altered cytokine profiles and reduced migratory and proliferative potentials. Consequently, in multiple animal models of ocular vascular damage, EPC obtained from normal individuals were able to attach to, and assimilate into, the damaged vasculature, while those from age- and sex matched diabetic patients lacked any regenerative ability (Caballero, 2007). For T2DM patients with AMI, deficiencies in their endogenous EPC make them minimally responsive to pharmacological approaches (Jarajapu, 2010) and unsuitable candidates for current approaches to autologous cell therapy. The goal of this project is to develop a novel stem cell delivery method that addresses the regenerative deficiencies of stem/progenitor cells of all patients after AMI, in particular higher-risk patients with T2DM. We will demonstrate the efficiency of this technology with cord blood- and peripheral blood-derived stem cells; the former demonstrate high migratory and regenerative properties, while those from peripheral blood show much lower migrating potential and should benefit more significantly from our approach (Aiuti, 1997). Success in enabling poorly migrating stem cells to revascularize and protect ischemic myocardium will warrant a Ph 2 application. Ph 2 work will focus on obtaining the preclinical data necessary for submission of an IND to perform PhI/II trials in patients with AMI. Patients will be randomized to receive conventional therapy vs. conventional therapy plus BiAb-armed stem cells and would include both diabetic and non-diabetic patients.
