Funding opportunities

"Stem Cell Therapies for Heart Failure"

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00704
Principle Investigator: 
Funds requested: 
$53 150
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Our multi-institutional program is dedicated to the treatment of heart failure, which has become a leading cause of death in California and the U. S. The high death toll continues to climb despite many significant recent advances in the medical treatment of heart failure. The disease is due to a debilitating loss and/or dysfunction of heart muscle cells (cardiomyocytes) in the injured heart. Most current therapies and clinical trials are not designed to regenerate these cells. Rather, they focus on boosting output of the failing heart and/or forestalling further decline. Our intention is to regenerate or replace the damaged cardiomyocytes and their supporting cells. Our consortium unites over 20 highly successful laboratories with expertise in cardiomyocyte stem cell biology, high throughput chemical library screening and drug discovery, biomaterials and bioengineering, cardiac imaging, heart failure therapeutics, and advanced clinical interventional cardiology. These groups will be organized into Basic Discovery, Translational, and Applied and Clinical research teams to bring two types of therapies from the research lab to the clinic. The first will be to replace damaged cardiomyocytes by transplantation of stem cell derived cardiomyocytes, either from embryonic stem cells (ESCs) or cardiomyogenic cells derived from the patient. The second will be to use stem and progenitor cells to develop drugs capable of stimulating regeneration in a patient’s heart from his or her own cells. It is likely that a successful therapy will combine these two approaches. Importantly, we will develop technology to deliver stem cell-derived cells to the heart in human patients and evaluate their survival and effects on function. The PI and lead investigators represent a multidisciplinary team consisting of basic research and clinical faculty, a number of whom hold chair, division chief or directorial positions in their institutions and have experience leading multidisciplinary projects. During the planning period, the team will carry out the following tasks: • Develop a comprehensive research plan, including specific aims to be jointly carried out and milestones to be achieved. • Develop a detailed plan for translating the basic findings to clinical and pharmaceutical environment that will address, in addition to scientific and medical issues, key financial, philanthropic, and legal hurdles. • Coordinate our clinical, pharmaceutical and device industry partners to speed along translation to clinic and pharmaceutical or biotech environment. • Coordinate management and fundraising initiatives and resolve intellectual property and contractual issues among the participating institutions • Partially compensate a chief operating officer to coordinate the activities of the consortium.
Statement of Benefit to California: 
Benefits will accrue to California through: 1. California heart disease patients will benefit from improved therapies. The numbers are staggering: Of the 60 million Americans who have cardiovascular disease, 5 million have heart failure [American Heart Association (AHA) Annual Report, http://www.americanheart.org]. In California, it is the most common diagnosis at hospital discharge for people over age 65 and the largest cause of mortality and morbidity, with an approximately 50% survival rate after 5 years. The cost estimates to treat heart failure vary widely but are considerable, ranging from $8 billion to over $400 billion annually in the US (AHA estimate is about $20 billion). According to the California HealthCare Foundation, the annual per capita cost for treatment in the state is $13,000 (Improving Quality of Care for Californians with Heart Failure, CHCF publication, 2002). Current therapies address heart function largely through pharmaceutical management (e.g. ACE inhibitors, diuretics, inotropic agents) but are not designed to replace or supplant the muscle cells that are lost or dysfunctional. The goals of our research program will address the underlying disease and thus have potential for alleviating pain and suffering of the patient population and their families as well as decrease the financial burden to the patients’ families, private insurers and state agencies. 2. Technology transfer to California institutions. Each of the participating institutions has seen and implemented a steady increase in technology transfer in the past decade. Based on these precedents, and the translational potential of our research goals, this program is likely to result in licensing of further technology to the corporate sector. This will have an impact on boosting the competitiveness of our state’s technology sector with the accompanying potential for creation of new jobs. 3. Enhanced ability of California institutions to recruit stem cell scientists. Already, we have seen a number of recruits from students to senior faculty as a result and this is likely to be enhanced by additional funding. Moreover, because of the translational nature of the research and resulting technology transfer to industry partners, the proposed disease-oriented research should have a similar impact on our biotechnology and/or pharmaceutical partners.
Review Summary: 
Executive Summary The objective of the proposal is to develop technology to deliver stem cell-derived cells to the heart in patients, and to evaluate cell survival and functional effects. The applicant proposes two approaches to bring to clinical trials: 1) to develop technologies to produce cardiomyocytes from human embryonic stem cells (hESCs) or from a patient’s own cells, and to scale up production and deliver biomaterials for transplantation; and 2) to develop drugs to mobilize a patient’s own progenitor cells to repair myocardial function through production of new cardiomyocytes and supporting cells. A successful therapy is hypothesized to combine these two approaches. Planning grant funding will be used to a) refine the organization of the research teams and the program’s specific aims and milestones; b) formalize tie-ins with corporate partners; and c) develop Institutional Review Board (IRB) protocols. Reviewers recognized the clinical significance of the congestive heart failure, which carries significant burden to the health system as well as to afflicted individuals. The current therapies of end-stage failure, implantation of a left ventricular assist device (LVAD) and cardiac transplantation, while effective in many patients are limited by the magnitude of the procedure, the availability of hearts and the need for immunosuppression. Clearly, alternative therapies would be welcome. Preliminary data from animal studies and the clinic are encouraging with regard to safety. Reviewers felt that the plan is ambitious, with the expected deliverables of both a clinical trial of induced cardiomyocytes and also small molecule leads for endogenous regeneration. One reviewer noted that a significant number of different diseases are mentioned in the proposal, and that it is not clear from the application which disease is the primary target. However, given the track record of the individuals and institutions involved it is reasonable to expect a subset of phase 1 trials within 5 years. One reviewer commented that to do both a drug and stem cell therapy in 5 years is dubious, but success in at least one approach is likely, and would be a benefit to the field. Reviewers concurred that the stem cell approach seemed clearly outlined in the proposal. However, it was not clear from the application how the small molecule approach would be accomplished, although reviewers noted the inclusion of subject-matter experts on the team. It was also less clear to one reviewer how the research will specifically translate into clinical trials. The proposal also touched on scale up, delivery, and imaging technologies, which would be important in both approaches. As associate director of a stem cell research center, the PI is skilled in managing and integrating the efforts of large groups of individuals towards a common goal. Very importantly, the PI has already assembled a skilled and respected team of individuals to lead the various efforts required to bring this project to fruition. Expertise of the lead investigators spans drug discovery, stem cell biology, bioengineering, cardiac imaging, clinical cardiology and clinical trial design. The planning phase was felt to be a thoughtful, collaborative and highly integrated approach that should lead to success. All reviewers noted that the team appears to already be working together, and this was felt to be a strength. A chief operating officer has been appointed to coordinate the planning process with the PI and the various team leaders. The planning process covered activities that would take the project to the clinic including: a) defining the organization of the research program and its specific aims and milestones; b) formalizing tie-ins with commercial biotechnology and device partners to speed translation of the research to human patients; c) meeting with FDA officials to outline clinical cardiology protocols. Overall, reviewers were enthusiastic for this mature concept, led by a well qualified PI. Some doubts remained that the team would be able to accomplish both approaches (cell therapy and small molecule strategies) in the allotted 5 year time frame, but noted that success in either approach would be a great benefit to the field. Reviewer Synopsis Objective: Develop technology to deliver stem cell-derived cells to the heart in patients and evaluate their survival and effects on function. They will develop two approaches to bring to clinical trials: (1) Develop technologies to produce cardiomyocytes from hESCs or from a patient’s own cells, transfer these to bioreactors to scale up production and deliver biomaterials for transplantation; (2) Develop drugs to mobilize a patient’s own progenitor cells to repair myocardial function through production of new cardiomyocytes and supporting cells. A successful therapy is hypothesized to combine these two approaches. The expertise of the lead investigators spans drug discovery, stem cell biology, bioengineering, cardiac imaging, clinical cardiology and clinical trial design. Planning grant funding will be used to a) refine the organization of the research teams and the program’s specific aims and milestones; b) formalize tie-ins with corporate partners; c) develop IRB protocols. Reviewer One Comments Concept: Although the overall focus here is on cardiovascular disease, the primary goal of the proposed work relates to congestive heart failure, which afflicts about 5 million people in the US and has a 5 year mortality of about 50%. The current therapies of end-stage failure, implantation of an LVAD and cardiac transplantation, while effective in many patients are limited by the magnitude of the procedure, the availability of hearts and the need for immunosuppression. Clearly, alternative therapies would be welcome, and preliminary data from animal studies and the clinic are encouraging with regard to safety and can be expected to achieve efficacy. The investigators plan to establish Basic Discovery, Translational, and Applied and Clinical Research teams to develop cell-based (transplantation of cells for replacement) and drug-based (drugs to stimulate endogenous regeneration) therapies. The goals are: 1. Develop technologies to produce cardiomyocytes from hESCs or a patient’s own cells using natural and small molecule regulators of differentiation; 2. Transfer the methods to bioreactors to scale up their production, and develop biomaterials for transplantation; 3. Develop technology to deliver stem cell-derived cells to the heart in human patients and evaluate their survival and effects on function through cardiac imaging; 4. Develop drugs to mobilize a patient’s own progenitor cells to repair myocardial function through the production of new cardiomyocytes and supporting cells. The expected deliverables are a clinical trial of induced cardiomyocytes and small molecule leads for endogenous regeneration. During the Planning Phase, they will a) define the organization of the research program and its specific aims and milestones; b) formalize tie-ins with commercial biotechnology and device partners to speed translation of the research to human patients; c) meet with FDA officials to outline clinical cardiology protocols. The plan is ambitious, but given the track record of the individuals and institutions involved it is reasonable to expect a subset of phase 1 trials within 5 years. Principal Investigator: As associate director of the NASCR Center, Dr. Mercola is skilled in managing and integrating the efforts of large groups of individuals towards a common goal. Very importantly, he has already assembled a skilled and respected team of individuals to lead the various efforts required to bring this project to fruition. Planning Approach: A COO, Dr. John Watson, has been appointed to coordinate the planning process with Dr. Mercola and the various team leaders. Each team will perform the following tasks: 1. Develop a comprehensive research plan, including specific aims and milestones. For each specific aim, the team will identify the laboratories that are best suited to carryout the research and then establish the scientific goals and milestones, personnel, equipment and budgetary needs. 2. For each specific aim, key scientific challenges will be identified that need resolution before the grant can be submitted. The team will then select laboratories that will carry out research to resolve these issues so that the aims in the final application will be cohesive and feasible. 3. Develop a detailed plan for translating the basic findings to clinical and pharmaceutical environment. Plans for moving the research from the basic to more translational and clinical laboratories and between the academic and corporate partners will be elaborated. Key financial and legal hurdles will be identified together with solutions. 4. The Applied and Clinical Planning Team will plan clinical protocols in consultation with IRBs and the FDA, and will identify patient populations and additional clinical partners if necessary. 5. Dr. Mercola and the COO will monitor progress of the Planning Teams and will serve as conduits from one team to the other. Frequent meetings of the entire planning organization, including new participants as identified, will be organized to advance the planning mission by coordinating efforts, critiquing plans and progress on program-wide initiatives that include: preparation of the final application, philanthropy, and resolving intellectual property issues between the 4 institutions and corporate partners. All in all this is a thoughtful, collaborative and highly integrated approach that should lead to success. Reviewer Two Comments Concept: • The proposal mentions a significant number of different diseases, and it is not clear from the application which disease is the primary target. • Approach one: optimization of differentiation protocols to differentiating cells to cardiac myocytes; strengths are the already existing expertise in this area, and that specific milestones like optimization in monolayer culture then transfer into a bioreactor, etc. are clearly outlined • Approach two: mobilization of endogenous heart progenitor cells; not clear to me how they will accomplish this, however there seems to be a lot of experts that may know how to do this • Even though many details are not presented, it appears like a mature concept. Principal Investigator: The PI, although not an MD, is a very experienced investigator with track record in leadership and establishing and fostering collaboration. Planning Approach: The planning approach describes an excellent organization with description of individual teams that seem to collaborate already, and it appears like a solid concept with investigators that are already working together. However, it is not clear how this research will specifically translate into clinical trials.
Conflicts: 

© 2013 California Institute for Regenerative Medicine