Clinical Trials within U.S.: Heart Disease

CARDIOVASCULAR DISEASE IS the number one cause of death in the United States. Cell therapy is being investigated at a rapid pace worldwide and may revolutionize contemporary cardiovascular disease treatment. Progress in this field is fueled by promising results in animal studies and a societal push for effective and potentially curative therapy. Stem cells can differentiate into nearly any mature cell phenotype and can self—renew indefinitely. Adult—derived “progenitor” cells have limited differentiation capability and cannot self—renew; however, these cells are more readily accessible and are not subject to moral/ethical debate. Bone marrow and peripheral blood circulating progenitor cells have been the focus of current human trials. Future trials will explore the therapeutic potential of other adult progenitor cell sources.

Initial emphasis on cell transfer to replace myocardium has recently shifted to paracrine modulation of myocardial remodeling, mechanical [Page 122]strengthening of scar tissue, and promotion of tissue survival. Human trials have demonstrated feasibility of a variety of cell—based approaches with modest short—term benefits. Cells from autologous (one's own self) and allogeneic (from donors) sources have been transplanted in patients with heart disease, using a variety of delivery approaches. Safety has been confirmed in nearly all cardiovascular cell therapy trials; however, important questions such as optimal cell type, dose, delivery method, and patient type remain.

Three clinical syndromes are principal targets for cell therapy approaches: myocardial infarction (MI), chronic myocardial ischemia, and cardiomy—opathy. Considerable overlap exists in the clinical presentation and pathophysiology of these syndromes; however, categorizing in this way is useful to demonstrate the rationale and study design of clinical trials. Cell therapy attempts to prevent heart enlargement following MI, develop new blood vessels and increase blood flow for chronic myocardial ischemia, and regenerate contractile heart muscle for cardiomyopathy causing heart failure.

Mechanisms underlying the benefits of progenitor cells observed in animal studies remain poorly understood. Transplanted cells may encourage the release of factors that locally activate adjacent native cells with beneficial effects. A few investigators suggest that cells “fuse” with native cells and thereby alter their behavior in some beneficial way. Others suggest that transplanted progenitor cells transdifferentiate and that the daughter cells become the cells of the target organ, such as heart muscle cells or blood vessels. Fusion and differentiation events are perhaps too rare to have meaningful treatment effect.

Several adult progenitor cell types have been studied, and many are identified by cell surface antigens measured by flow cytometry. CD34+ cells and CD133+ cells identify endothelial progenitors and may be isolated from bone marrow, adipose tissue, peripheral blood, and umbilical cord. These cells may promote new blood vessel growth in areas of ischemia. Mesenchymal stromal cells (MSCs) may induce a therapeutic effect via para—crine mechanisms. Skeletal myoblasts represent an abundant autologous source of cells that show a contractile phenotype when transplanted into the myocardium. In addition, resident cardiac stem cells have been discovered to reside in protected niches in the heart. Early—phase clinical trials using skeletal myoblast and resident cardiac stem cell transfer following ex vivo expansion are ongoing.