Cardiovascular disease is the leading cause of U.S.morbidity and mortality, and 10% of the U.S.population over 65 y has been diagnosed with chronic heart failure (CHF). Transplantation of stem cells improves left ventricular function (LVEF) in animal models of acute myocardial infarction (AMI)and CHF. Recent evidence shows that this strategy with whole bone marrow (wBM)preparations may improve LVEF in patients with AMI. Studies with wBM and skeletal myoblasts (SKMB) have yielded promising results suggesting improvement of LVEF in CHF patients. To further translate the findings of our group and others into clinical practice we seek to participate in the Cardiovascular Cell Therapy Research Network (CCTRN). This network will lead the field in developing and implementing cell therapy for the treatment of cardiac dysfunction. Great advances have been achieved towards developing, understanding and implementing cell therapy. Recent findings in clinical trials using wBM have highlighted the need for well planned trials that focus on appropriate populations, have rigorous cell preparation, and ask important questions critical to advance the field while assuring patient safety. We believe a collaborative center in Greater Cleveland would be an excellent site for this NHLBI CCTRN. Cell based clinical trials already performed in the Cleveland area include the RECOVER trial that studied the role of G-CSF in patients with AMI and moderate to severe LV dysfunction, and participation in completed and on-going multi-center clinical trials testing SKMB in CHF. This proposal represents a cohesive group of investigators interested in developing a center at Case Western Reserve University that leverages the broad expertise that is present in the Greater Cleveland area including: expertise in multi-center cardiovascular trials, non-invasive cardiac imaging, and non-invasive arrhythmogenic risk assessment. Our Network site will draw patients from diverse hospital centers in the community as well as tertiary care centers. Our group has been studying the potential of allogeneic multipotent adult progenitor cells (MAPC)-based therapy for improving LVEF following AMI. Allogeneic MAPC therapy for acute Ml is enticing because MAPC can undergo expansion in culture to >70 doublings generating, from a single donor, a thousand doses that could be available whenever the patients present.
In SPECIFIC AIM 1 we will determine the efficacy of allogeneic MAPC in patient with AMI. We also have a program to define the mechanism of stem cell homing to injured myocardium. We have shown that the transient re-establishment of the stem cell homing molecule SDF-1is sufficient to induce homing, vasculogenesis and recovery of myocardial function in preclinical models of CHF.
In SPECIFIC AIM2 we will test the feasibility of cell based gene therapy and demonstrate whether transient re-establishment of signaling for stem cell homing to myocardial tissue is an efficacious therapy for patients with Class III CHF.
|Penn, Marc S; von Recum, Horst A (2011) A tale of 2 biologies: stem cell patch: myocardial interactions are critical for myocardial regeneration. J Am Coll Cardiol 58:2128-9|
|Penn, Marc S; Anwaruddin, Saif; Nair, Ravi et al. (2009) From mice to men. Commonalities in physiology for stem cell-based cardiac repair. J Am Coll Cardiol 54:2287-9|