Executive Summary The goal of this proposal is to improve left ventricular cardiac function and reduce cardiovascular death and heart failure in acute myocardial infarction or dilated cardiomyopathy by treating with human embryonic stem cell (hESC)-derived cardiomyocytes. The goals for the planning process are: 1) to develop and organize a team to move hESC transplantation from animal models of myocardial infarction and dilated cardiomyopathy into clinical trials; 2) to determine and overcome the major hurdles for the transplantation of hESC into heart failure patients; 3) to develop a structure in which the specialists communicate with each other; and 4) to define milestones to be met to begin clinical trials. Reviewers felt the proposal concerns a complex, but important research target. Clinical significance of the target was recognized by reviewers, as congestive failure continues to be a major public health issue, with a 50% mortality rate over a five year period. Current treatment ultimately depends on availability of a reasonably histocompatible heart for transplantation. Reviewers felt that hESC-derived cardiomyocytes are a logical and well-posed remedy especially for acute and healed myocardial infarction (MI), but noted that the existing data supporting treatment of dilated cardiomyopathy are less convincing than for treatment of MI. Reviewers were mixed in their opinions of the concept plan, and questioned whether it was realistically achievable within the 5-year time frame. While some felt it to be thorough and a strength of the application, another noted that it lacked several key elements that would need to be addressed satisfactorily for first-in-human studies to transpire, including: bioprocessing, ramp-up, and purification of cardiomyocytes without genetic markers. Furthermore, tumorigenicity is dealt with cursorily. In summary, the problem formulation was felt to be skeletal, by comparison to more competitive applications for a planning grant. Reviewers felt that the principal investigator (PI) was well-qualified to lead this potential team. The PI has a distinguished history of contribution to the literature on heart failure. He/She has been involved in studies of transplantation of fetal myocytes, and more recently, studies of human mesenchymal stem cells (hMSCs) and hESCs. The PI has also been an active participant in clinical trials and has the skills to move the research from basic studies through to clinical application. The planning approach will include meetings of multi-institutional groups of specialists in relevant scientific disciplines, and will also include experts in the area of regulation and in GMP. The team hierarchy and members have been identified, there is a good history of collaboration among the members, and the environment was felt to be very good. Meetings will deal with the obstacles to be overcome in the research plans. While it is likely that the team will be ready to prepare a Disease Team Research application, there is concern over the nature of the obstacles to be overcome in the time allotted. Reviewer Synopsis The goal is to improve LV function and reduce cardiovascular death and heart failure in acute myocardial infarction or dilated cardiomyopathy by treating with hESC-derived cardiomyocytes. The aims are: 1) To develop and organize a team to move hESC transplantation from animal models of myocardial infarction and dilated cardiomyopathy into clinical trials. 2) To determine and overcome the major hurdles for the transplantation of hESC into heart failure patients 3). To develop a structure in which the specialists communicate with each other. 4). Define milestones to be met to begin clinical trials. Plans include meetings of multi-institutional groups of specialists in 1) cell development, 2) in-vivo animal model testing, 3) clinical research, 4) regulatory issues and, 5) an advisory committee. Meetings will focus on issues whose solutions are needed to move injection of hESCs from basic science into clinical trials and on optimizing trial design. Reviewer One Comments Concept: This proposal seeks to develop a team approach to the use of hESCs for heart failure. The identification of obstacles and needs is logical but just skims the surface, lacking several key elements that would need to be addressed satisfactorily for first-in-human studies to transpire, including: bioprocessing, ramp-up, purification of cardiomyocytes without genetic markers, etc. Tumorigenicity is dealt with cursorily. The problem formulation is regrettably skeletal, by comparison to more competitive applications for a planning grant. Heart failure is well posed as a target, and current trials have not been effective for reasons noted in the proposal. hES cell-derived cardiomyocytes are logical and well posed as a remedy. This may be less true for dilated cardiomyopathy than for acute and healed infarction; I do not think the existing data are adequate on this point. Because hES cells will require immunosuppression (unless immune rejection is overcome in other ways), there is concern whether the preclinical benefits are large enough to justify a clinical trial. Principal Investigator: Professor Kloner is a recognized cardiovascular physiologist and translational researcher. His leadership abilities are strong. He has published actively on regenerative medicine, although the work is often less innovative than in more competitive proposals, and this is reflected by the journals in which relevant papers of the group have appeared. Planning Approach: It is not clear enough how some of the named partners would be engaged, e.g., UCSD. There is insufficient justification or risk/benefit calculation for the proposed use of allogeneic hESCs necessitating immunosuppression. The proposal incorporates no fallback or parallel platform technology. It is difficult to identify a portfolio of competitive advantages that would position this group to surpass others in the same therapeutic space. Reviewer Two Comments Concept: The target is a complex one, but important and its achievement is plausible. Congestive failure continues to be a major public health issue, with a 50% mortality over a five year period, and whose treatment ultimately depends on availability of a reasonably histocompatible heart for transplantation. Questions to be answered by the investigative team within 3 - 4 years of onset of preclinical translational research, include: “1) When is the optimal time to inject the cells following coronary occlusion? 2) What is the optimal route of injection - via the coronary arteries or directly into the myocardium? 3) What is the optimal immunosuppressive regimen? 4) How long do the grafts persist? 5) Do the cells develop an adequate blood supply? 6) Are adjunctive cocktails of growth factors, anti-apoptotic factors, and pro-survival factors necessary for graft survival? 7) What is the long term (> 6 months) effect on cardiac function - global, regional, and left ventricular remodeling? 8) What are the long term effects on arrhythmias? 9) Do the cells remain electrically connected to the remainder of the heart long term? 10) Can adequate number of beating cells be scaled up for clinical use? 11) While we did not observe teratomas in our initial study (perhaps because the cells we injected had already differentiated) long term surveillance for teratomas will be needed. 12) Can cell retention be improved?” This is a daunting list of questions, the answers to which are essential if the program is to move to the clinic. There are concerns that the answers are not achievable within this limited time frame. Principal Investigator: Dr. Kloner has a distinguished history of contribution to the literature on heart failure. The PI has been involved in studies of transplantation of fetal myocytes, and more recently, studies of hMSCs and hESCs. He has been an active participant in clinical trials and has the skills to move the research from basic studies through to clinical application. Planning Approach: The team hierarchy and members have been identified. There is a good history of collaboration among the members. Meetings will deal with the obstacles to be overcome in the research plans and also will include experts in the area of regulation and in GMP. While it is likely that the team will be ready to prepare a Disease Team Research application, there is concern over the nature of the obstacles to be overcome in the time allotted. Reviewer Three Comments Concept: -classical concept of cell replacement in the heart -very mature project Principal Investigator: - very experienced investigator; leadership of bigger projects and clinical trials Planning Approach: -strength: very experienced investigator -very good environment