Funding opportunities

Executive Summary This is a proposal to establish a disease team for developing cell therapy for the treatment of ischemic cardiac injury resulting from heart attack. The proposed team will design a program to devise approaches for generating autologous human induced pluripotent stem (iPS) cells from patients and develop strategies to use these cells for myocardial repair, restoration of local microvasculature, and modulation of tissue microenvironments. Efforts will be made to define needed expertise and resources, highlight regulatory issues, and identify technologies required for advancing the cellular therapy toward clinical testing. This proposal is focused on the important goal of treating cardiovascular disease, a leading cause of mortality and morbidity in the U.S. Although some forms of cellular therapy for repairing myocardial infarcts are already in clinical trials, serious issues concerning efficacy and the source and identity of therapeutic cells remain unresolved. The proposed goal of this study is significant and clearly defined. However, the reviewers had serious concerns that the proposal was premature. In particular, the use of patient-specific iPS cells (which could alleviate issues of immune rejection) will require extensive development, optimization, and testing, and it is unclear how quickly (if ever) this approach will be translatable into a useful and clinically relevant cell source. Prospects for clinical use of such cells within five years appear extremely doubtful. The PI is an experienced clinical cardiologist and investigator who has expertise with cellular therapy and clinical trials. He/she has experience with both adipose-derived stem cells and skeletal myoblasts, and has good insight into the benefits and risks of cell therapy. The planning process is a major problem with the application. Although a multidisciplinary team with appropriate expertise has been identified, there exists no formal organization or outline of how the planning process might proceed. It is unclear how the proposed symposium and meetings will lead to a cohesive and robust planning process and a timely proposal submission. Reviewer Synopsis Clinical trials testing efficacy of cell therapy to the heart after ischemic injury have had variable results. Aims are to 1) develop techniques to create approvable, autologous human induced pluripotent stem (hIPS) cells using GMP practices, 2) develop strategies to restore local microvasculature, 3) develop bioengineering strategies to modulate tissue microenvironment. Concurrently, technologies will be developed to differentiate and isolate cardiovascular progenitor cells from hIPS cells and to test safety and efficacy in large animal models of ischemic cardiac injury. They will also attempt to regenerate damaged coronary vasculature endothelium after ischemic insult and promote neovascularization of tissue reconstituted by cell therapy. Additional efforts will be made to create a local microenvironment in heart that is favorable to cell survival and engraftment using biodegradable scaffolds. Pilot funding will further define expertise, resources, regulatory issues and technology needs Reviewer One Comments Concept: Repairing/regenerating infarcted myocardium has been a major goal of stem cell therapy and has met with reasonable results regarding safety but with limited success (more statistical than physiological) with regard to efficacy. The proposed project is a laudable one in that the investigators plan to develop a clinically testable autologous pluripotent stem cell source, develop strategies to restore microvasculature, and modulate tissue environment and to have regulatory-approvable cells available within 4 years. However, not enough is presented regarding the maturity of the investigators’ own approach (and for that matter the general field’s success and approach) to have a great deal of confidence in readiness for delivery in 5 years. That is, the vaguest skeleton of a plan is presented rather than a robust one, and the investigators and collaborators needed to flesh it out have been named, but no organization of their efforts appears to have begun. Indeed the most positive aspect of the work so far has been evaluating adipose-derived stem cells as a treatment for chronic ischemia, which is currently in clinical trial in Europe. Principal Investigator: The PI has had a record of achievement in bringing stem cells from the basic laboratory to clinical trial. He has worked not only in the area of adipose-derived stem cells, but also with skeletal myoblasts. As such, he has a good understanding of the benefits and risks of cell therapy. Planning Approach: This is the major problem with the application. A team has been named with appropriate expertise in the stem cell and bioengineering arena. But it appears that there has been no formal organization to date. While collaborations do exist among these individuals, we are told only that planning meetings will be set up and a symposium held. While a number of distinguished stem cell scientists have been invited as speakers, which of them will be in fact advisors/collaborators and which have merely or will merely pass through has not been defined. In other words, this appears to be a proposal to plan a meeting or meetings to then make a plan. While the reviewer understands the need and logic for such an approach, its contribution to a cohesive planning process and an award submission appears tenuous. Reviewer Two Comments Concept: The disease target is very significant and specific (heart attack). The goals are well defined. However, focused on patient specific cell therapy, this is a very new technology, and thus it is unclear how quickly (if ever) it will translate into a useful and clinically relevant cell source. It may be too premature to have this as an entire aim, but it is obviously very timely strategy. The goal of restoring local microvasculature is an interesting concept. Also novel and interesting is the bioengineering component that will be very critical for cell applications in the cardiovascular system. Principal Investigator: The PI is an experienced investigator who has significant expertise in the field of cell therapy. He is a clinical cardiologist. Planning Approach: These efforts are mainly focused on recruitment of internal and external expertise.