Cardiac Regenerative Therapy Using Gene-Edited Stem Cells to Improve Transplantation Outcomes

About This Grant

Project Summary Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Significant loss of cardiomyocytes from myocardial infarction (MI) can cause progressive deterioration of cardiac function. Many patients do not recover despite optimal medical therapy and develop progressive adverse structural and electrical remodeling that leads to heart failure (HF). HF remains a deadly syndrome, with 5-year mortality of 45- 60%. Thus, there is a compelling need to seek new options for patients in end-stage HF. Since adult cardiac myocytes are unable to proliferate sufficiently to replace damaged tissue, stem cell therapy represents a promising approach to generate new functional myocardium and stimulate neoangiogenesis. However, poor survival and retention of donor cells in the hostile post-injury environment remain major challenges for cardiac stem cell transplantation. Our compelling data in a murine post-MI model demonstrate that inflammation is a key driver of transplanted stem cell loss. The overarching goal of this proposal is to improve transplantation outcomes in end-stage HF by modifying both the donor cells and host environment, targeting genes involved in inflammatory pathways. This proposal directly addresses inflammation-mediated cell death that severely impedes cardiac stem cell therapy. Successful completion of the proposed studies will advance personalized cardiovascular care and facilitate the translation of transplantation therapies from bench to bedside.