REQUEST FOR INFORMATION ON THE TRANSLATION OF CELL-BASED THERAPIES FOR CARDIOVASCULAR DISEASES RELEASE DATE: April 9, 2004 NOTICE: NOT-HL-04-108 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/index.htm) Response Due Date: June 1, 2004 PURPOSE The NHLBI is soliciting comments and ideas on approaches to translate and implement cell-based therapies for the treatment of cardiovascular diseases. BACKGROUND Cardiovascular disease, including hypertensive disease and myocardial infarction, leads to loss of cardiac tissue through apoptotic and necrotic cell death. The remaining myocytes are unable to reconstitute the lost tissue, and the diseased heart deteriorates functionally with time. Current options for treating these conditions suffer from limitations and are primarily directed at limiting disease progression rather than repair and restoration of healthy tissue and function. In light of the limited efficacy and co-morbidity of these current treatment options, alternative, additional long-term therapeutic strategies are needed. Cardiac repair is one potential new therapeutic option for repairing damage to the heart resulting from myocardial infarction or ventricular remodeling. Through cellular therapies, the concept of "growing" heart muscle and vascular tissue and manipulating the myocardial cellular environment may revolutionize the approach to treating heart disease. Recent studies suggest that stem cells resident within the bone marrow or peripheral blood can be recruited to the injured heart. Two of the most widely used cell types for cardiac repair today are skeletal muscle-derived progenitors, or myoblasts, and bone marrow-derived progenitors. Both cell types share advantages over other cells proposed for cardiac repair in that they are readily available, autologous, and more easily expanded in vitro. Adding to this mix is accumulating evidence that the heart contains resident stem cells that can be induced to develop into cardiac muscle and vascular tissue. Transplantation of both skeletal myoblasts and bone marrow-derived stem cells into the region of infarcted myocardium results in improved myocardial function in both the murine and porcine infarct models. The injection of stem cells and bone marrow stimulating cytokines in model systems produces functional cardiac benefit. Studies employing ischemic limb models indicate that cell therapy with endothelial progenitor cells can successfully promote neovascularization of ischemic tissues. A similar strategy applied to a model of myocardial ischemia in the nude rat demonstrates that transplanted human endothelial progenitor cells localize to areas of myocardial neovascularization, differentiate into mature endothelial cells, enhance neovascularization and are associated with preserved left ventricular function and diminished myocardial fibrosis. Genetic modification of progenitor cells prior to transplantation has also been used to enhance survival of the implanted cells. However, the issues surrounding autologous cell-based therapy for cardiovascular disease are substantial. For muscle repair, cells must incorporate themselves into the heart, survive, mature, and electromechanically couple and ultimately increase contractile function. In terms of stimulating the formation of new blood vessels to increase blood flow to affected regions, cells must develop vascular beds complete with smooth muscle and endothelium that connects and conducts blood flow. In order for cell therapy to be widely clinically applicable, the optimal cell has to be compatible both mechanically and electrically with the host myocardium. An additional cell-based therapy research area which shows promise is the mobilization of progenitor cells in vivo using cytokines, and subsequent homing of the mobilized cells to damaged myocardium. Injection of cytokines and other chemotactic molecules into the heart also shows promise for enhancing homing of progenitor cells mobilized in vivo or injected into the vasculature. The concept of transplanting autologous cells into a damaged heart has received significant attention, both in scientific circles and the popular press. The most exciting and promising clinical studies to date have evaluated autologous stem cell transplantation soon after acute myocardial infarction. Ongoing clinical trials in Europe and elsewhere are examining the safety and efficacy of autologous skeletal myoblast transplantation in patients as an adjunct to coronary artery bypass surgery. Published studies have used bone marrow or peripheral circulating progenitor cells that were injected down the infarct-related artery and a randomized controlled trial has shown improvement of left ventricular ejection fraction with bone marrow cell transfer into the infarct related artery. The NHLBI has launched a number of programs to foster research on basic, pre-clinical studies of stem cells. However, the scientific community and the public are now looking to apply these fundamental basic science observations to the treatment of cardiac diseases. Careful consideration and direction are needed to safely and effectively translate cell-based therapies into medical practice. INFORMATION REQUESTED The NHLBI seeks your help in identifying (a) the major opportunities to develop and apply cell-based therapies to heart disease; (b) the critical needs to enable progress, and the barriers that may inhibit it; and (c) practical and effective ways to meet the needs, overcome the barriers, and take full advantage of the opportunities. Your thoughts, ideas, and suggestions will be used to help guide future Institute activities designed to expedite the translation of cell-based therapies the treatment of cardiovascular disease and efforts to improve patient care. Respondents are asked to comment on one or more of the issues listed below, but should not feel compelled to address all of them. 1. Please identify the major needs for, and barriers to, translating cell- based therapies to cardiovascular disease and medicine. Specific suggestions concerning steps or requirements that must be met in order to translate cell- based therapies for cardiovascular disease would be helpful. 2. Please suggest approaches the NHLBI can take to meet the needs, overcome the barriers, and take full advantage of the opportunities. Any specific suggestions regarding expertise, capabilities, and resources needed would be valuable. 3. Please comment on the selection of cell type to be used for cell-based therapies for cardiovascular disease. Provide specific suggestions regarding the use of autologous versus allogeneic cells, and the need for isolation, purification, and characterization of the cells. 4. Please consider and comment on safety and regulatory issues that are likely to be encountered in translating cell-based therapies. Please include ideas on how these issues can be addressed. 5. We would appreciate any additional views or opinions that you think would be useful. RESPONSE AND PROCESS Responses in any of the areas are welcome; respondents should not feel compelled to address all items. Please respond no later than June 1, 2004. Responses will be compiled and shared with our advisory committees. We look forward to your thoughts, opinions, and suggestions and hope you will share this document with your colleagues. Thank you very much for your help. To respond, please link to the online form in the NHLBI Grants and Contracts page under Funding, Training and Policies section of the Information for Researchers area on the NHLBI Home Page http://www.nhlbi.nih.gov/funding/inits/rfi_cellbased.htm), or send a letter, fax, or e-mail to the following address: NHLBI/DHVD Data Coordinator c/o Ms. Tawanna Meadows Two Rockledge Centre 6701 Rockledge Drive Suite 9044 , MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-1802 FAX: (301) 480-1335 E-mail: DHVDdata@nhlbi.nih.gov
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