The present planning grant application lays the groundwork for a collaborative heart disease regenerative medicine team. We plan to develop sequential preclinical and clinical investigations directed at regenerative stem cell-based approaches to treating the following major cardiovascular diseases: heart attack and its sequelae; congestive heart failure; and heart block requiring a pacemaker. The basic foundation necessary to justify focused preclinical studies has been achieved by members of the collaborative team and by investigators elsewhere. We will plan detailed milestone-driven studies aimed at direct clinical applications in the above-mentioned cardiovascular diseases. Autologous adult cardiac stem cells (CSCs) will be used to treat myocardial infarction as well as cardiomyopathy. Cell delivery will be via catheters like those used to perform angioplasties on diseased coronary arteries. This work needs minimal additional preclinical work in large animals in order to be ready for regulatory filings in anticipation of human studies. To treat heart block, we will develop human embryonic stem cell (hESC)-derived biological pacemakers as a clinical product. Work to date has demonstrated feasibility at the proof-of-concept level, but preclinical studies in large animals will be required in preparation for an IND filing. We request funding to plan and establish detailed protocols to accomplish these studies, which will utilize existing facilities, and will leverage the resources and expertise of the collaborative team. Anticipated team members include experts in stem cell biology, clinical cardiologists and surgeons, imaging physicians, and leaders in clinical trial design. The planning grant will be used to obtain appropriate consultative expertise, to support collaborative team meetings, and to carve out time for the PI to prepare the definitive proposal.
Few families in California are not impacted by heart disease. Cardiovascular disease remains the leading cause of death and disability in Americans—on average, cardiovascular disease kills one American every 37 seconds. The death toll from cardiovascular disease is greater than that for cancer, chronic respiratory diseases, accidents, and diabetes combined. Death rates have improved, but new treatments are urgently needed. Aside from the human costs, cardiovascular disease exacts a tremendous fiscal toll: the American Heart Association estimates that the total costs of cardiovascular disease in the United States will approach one-half trillion dollars in 2008. All taxpayers must bear the economic burden of resulting death and disability. Clearly, virtually all Californians stand to benefit, directly or indirectly, from the development of more effective treatments of cardiovascular disease. Heart disease is a particularly good target not just because of the magnitude of the public health problem, but also because heart muscle does not ordinarily regenerate once it has been destroyed by heart attacks and other types of damage. If our studies are successful, we may offer a cost-effective way to reduce the tremendous damage to Californians inflicted by major types of cardiovascular disease. This in turn may also reduce the economic burden presently borne by taxpayers who support the health care systems in California. In addition to the public health benefits, spinoff technology developed by this disease team will benefit existing California-based biotechnology companies, leading to fuller employment and an enhanced tax base.
In this proposal, the applicant proposes to assemble a team that will target three major cardiovascular diseases – myocardial infarction (MI), cardiomyopathy, and bradycardia, although the project does not yet have a specific focus. The team will develop sequential preclinical and clinical investigations directed at regenerative stem cell-based approaches. Autologous adult cardiac stem cells will be used to treat myocardial infarction as well as cardiomyopathy. To treat heart block, the team will develop human embryonic stem cell (hESC)-derived biological pacemakers as a clinical product. Anticipated team members include experts in stem cell biology, clinical cardiologists and surgeons, imaging physicians, and leaders in clinical trial design.
Reviewers noted that two potential therapeutic targets are addressed in the proposal, and that they were at very different stages of readiness for the clinic. The first is regeneration and repair of the heart, in cases of MI and cardiomyopathy. This target has seen extensive preclinical work by this and other groups and some clinical work as well. It is a target that is ready for clinical planning, and is likely to be in the clinic in 5 years. The other target, the biological pacemaker, is very much in the preclinical phase and planning revolves solely around long-term studies in animal models. Reviewers felt that it is too early to deterimine whether clinical studies will be possible in 5 years, as this outcome awaits the animal studies proposed.
Both clinical problems addressed in the proposal are important. Myocardial repair and regeneration are focused on the population with ischemic heart disease and with cardiac failure, for which existing clinical approaches are good to marginal. Biological pacing has a niche target population: electronic pacemakers are excellent but not “perfect” therapies, and a biological alternative could be an improvement. It was unclear to reviewers that benefits of the proposed use of hESC-derived biological pacemakers currently outweigh the risks of lifelong systemic immunosuppression.
Reviewers felt that the PI is well qualified to lead this team to a successful outcome. The PI is one of the world leaders in cardiovascular disease research, who has rapidly distinguished himself as a major contributor to the translational pipeline for cardiac stem cell biology. The PI has headed large administrative and research efforts, and is in an excellent environment to support a multidisciplinary effort. Enthusiasm was diminished slightly by the weakness of underlying stem cell biology at the institution, by comparison with the most competitive institutions in California. Building bridges to other partners is encouraged for this aspect. One reviewer commented that the 5% PI effort indicated in the proposal might not be enough in view of the amount of work that needs to be covered.
Reviewers were mixed in their opinions of the planning approach. The planning process as presented defines a series of questions that need to be addressed and resolved:1) how the team can best work together, 2) what preclinical studies are required, 3) what are the key regulatory considerations, and 4) how the academic researcher and biotech company would interact. One reviewer felt that the plan was not well developed at this stage, and that these questions should already have been addressed. Another reviewer pointed out that this individual has been at the applicant institution for only one year, and the fact that this proposal and team could be assembled so quickly was impressive. Research infrastructure was adequate for the proposed studies, and collaboration with California biotechnology companies is also being considered. All reviewers commented that the only thing lacking from the approach would appear to be some consideration of availability and sources of GMP grade facilities and materials.
In summary, reviewers felt this was an excellent proposal, though the scientific maturity of the two proposed therapeutic targets was significantly different. The panel had great confidence in the PI’s ability to bring together a successful cardiovascular disease team.
Reviewer One Comments
There are two targets in this proposal: one is regeneration and repair of the heart. This target has seen extensive preclinical work by this and other groups and some clinical work as well. It is a target that is ready for clinical planning, and is likely to be in the clinic in 5 years. The other target, the biological pacemaker, is very much in the preclinical phase and planning revolves solely around long-term studies in animal models. It is too early to say whether clinical studies will be possible in 5 years, as this outcome awaits the animal studies proposed. Both problems dealt with are important. Myocardial repair and regeneration are focused on the population with ischemic heart disease and with cardiac failure, for which existing clinical approaches are good to marginal (with only transplantation available as a last-ditch therapy for high grade cardiac failure). Biological pacing has more of a niche population as its target: electronic pacemakers are excellent albeit not “perfect” therapies, and a biological alternative could be an improvement.
The PI is one of the world leaders in cardiovascular disease research. As editor of Circulation research and Chief of Cardiology at Hopkins he cemented his reputation and his move to Cedars-Sinai should avail him of further opportunities to move his research forward. He has headed large administrative and research efforts (a SCOR team, a Reynolds Center, and NHLBI-based Proteomics Center and Cell-based Therapy Center) and is well-qualified to lead a group such as the one proposed to a successful outcome.
All members of the team thus far organized are from Cedars-Sinai. It appears that one of the purposes of the planning procedure will be to bring together individuals from outside institutions (identities not yet specified) in the research process. All facilities for the studies are apparently in house. Collaboration with California biotechnology companies is also being considered.
The goals of the planning process are:
• To define means whereby the Team can best work together towards the overall objectives.
• To plan preclinical studies that may be required to advance towards regulatory filings.
• To anticipate and address prospectively the key regulatory considerations in planning early-phase clinical studies.
• To effectively address such regulatory considerations in the design of clinical protocols.
• To differentiate the CIRM Disease Team efforts from existing funding from NIH and the Donald W. Reynolds Foundation, while effectively leveraging such existing funding to help achieve the CIRM Disease Team goals.
• To explore means whereby academic researchers can work with, and leverage the expertise of, biotechnology company personnel in order to advance more rapidly towards a stem cell-derived therapy.
Satisfaction of these goals should lead to preparation of a Disease Team Research Award. The only thing lacking from the approach would appear to be some consideration of availability and sources of GMP grade facilities and materials.
Reviewer Two Comments
• A list of consultants and subcontractors remains to be determined, but certainly will be required for at least four areas: stem cells, FDA regulation, grant preparation, and research coordination. The fact that these consultants have not yet been identified represents a weakness for this proposal. (Reviewers were reminded that a fully named team was not a requirement of the RFA)
• Although I’m sure obvious to the PI the issue of GMP facilities has not been addressed and needs to be dealt with.
• Another strength is the fact that clinical areas from cell extraction, delivery, and clinical follow-up have all been adequately included. This mitigates some of the lack of maturity of the proposal itself.
• PI dedicates a 5% effort, which might not be enough in view of area that needs to be covered.
• The PI is a world leader in his field with a tremendous record of publications, which therefore clearly has the skill and talent to manage this project, and that fact alone, in addition to the environment represents my high enthusiasm reflected by my score.
• It can be argued that existing pacemakers are adequate and thus the formation of a biological one might not be a priority. However, this is a major talent of the PI represents a strength of this project.
• The planning process as presented defines a series of questions that need to be addressed and resolved. It is not well developed at this stage.
• There are four questions that need to be addressed: 1) how the team can best work together, 2) what preclinical studies are required, 3) what are the key regulatory considerations, and 4) how would the interaction between academic researcher and biotech company work. It seems that at this stage, these questions should already have been answered.
• The entire team is located at the same institution with the exception of on collaborator in Israel.
• Therefore, while the rationale of the project is high, the coordination among the team members remains immature.
Reviewer Three Comments
The present application seeks a planning award for further development of the cardiac regenerative medicine team at Cedars Sinai, newly occasioned by the recruitment of Eduardo Marbán. The elements are highly auspicious, and no better justification for a planning award can be envisioned than the scenario here, of highly able new leadership plus the need for the nascent team to coalesce.
Professor Marbán is a world-class cardiac molecular biologist who has rapidly distinguished himself as a major contributor to the translational pipeline for cardiac stem cell biology. His intellectual skills, organizational skills and leadership abilities are amply proven, as measured in particular by his transformative stewardship of the leading cardiovascular research journal and by several large-scale grant awards including an NIH Specialized Center for Cell Therapy and a Reynolds Foundation Center.
The steps for successful implementation of first-in-human studies have received meticulous attention with much nuance of thought. As mentioned, the case for a planning grant is especially strong in this circumstance. The clinical targets are well-balanced overall, with regeneration after myocardial infarction being seen as best-posed for a human trial within five years, in light of present knowledge. Because the cells to be used are autologous, this application overcomes many hurdles facing hESCs. In contrast, the proposed use of hESC-derived biological pacemakers may not yet have been made convincing enough to justify lifelong systemic immunosuppression. This is only a minor weakness, and taken in context with the more immediately achievable targets, this does not affect this reviewer’s score. Enthusiasm was diminished slightly by the weakness of underlying stem cell biology at the institution, by comparison with the most competitive California programs, even taking Dr Marbán’s arrival into account. Building bridges to other partners is encouraged for this aspect.