Funding opportunities

Pluripotent Stem Cell–Based Therapy for Heart Disease

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00671
Principle Investigator: 
Funds requested: 
$53 972
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Five million people in the U.S. suffer with heart failure, resulting in ~60,000 deaths/year at a cost of $30 billion/year. Heart failure occurs when the heart is damaged and becomes unable to meet the demands placed on it. Unlike other organs, the heart is unable to fully repair itself after injury. One of the common causes for the development of heart damage is a heart attack. After a myocardial infarction (heart attack), irreversible loss of contracting heart muscle cells occurs, resulting in scar formation and subsequently heart failure. Current therapies designed to treat heart attack patients in the acute setting include medical therapies and catheter-based technologies that aim to open the blocked coronary arteries with the hope of salvaging as much of the jeopardized heart muscle cells as possible. Unfortunately, despite advances over the past 2 decades, it is rarely possible to rescue the at-risk heart muscle cells from some degree of irreversible injury and death. Attention has turned to new methods of treating heart attack and heart failure patients in both the acute and chronic settings after their event. Heart transplantation remains the ultimate approach to treating end-stage heart failure patients but this therapy is invasive, costly, some patients are not candidates for transplantation given their other co-morbidities, and most importantly, there are not enough organs for transplanting the increasing number of patients who need this therapy. As such, newer therapies are needed to treat the millions of patients with debilitating heart conditions. Recently, it has been discovered that stem cells may hold therapeutic potential for these patients. Experimental studies in animals have revealed encouraging results when pluripotent stem cells are introduced into the heart around areas of myocardial infarction. These therapies appear to result in improvement in the contractile function of the heart. However, numerous questions remain unanswered concerning the use of pluripotent stem cells as therapy for patients with heart attack and heart failure. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells grow and divide indefinitely while maintaining the potential to develop into many tissues of the body, including heart muscle. They provide an unprecedented opportunity to both study human heart muscle in culture in the laboratory, and advance the possibility of their use in therapy for damaged heart muscle. We have developed methods for identifying and isolating specific types of human ES and iPS cells, stimulating them to become human heart muscle cells, and delivering these into the hearts of rodents that have had a heart attack. This research will refine and advance such approaches in small and large animals, develop clinical grade cells for use, and ultimately initiate clinical trials for patients suffering from heart disease.
Statement of Benefit to California: 
More than 90,000 people in California suffer with heart failure, at a cost of ~$540 million/year. Heart failure occurs when the heart is damaged and becomes unable to meet the demands placed on it. Unlike other organs, the heart is unable to fully repair itself after injury. One of the common causes for the development of heart damage is a heart attack. After a myocardial infarction (heart attack), irreversible loss of contracting heart muscle cells occurs, resulting in scar formation and subsequently heart failure. Current therapies designed to treat heart attack patients in the acute setting include medical therapies and catheter-based technologies that aim to open the blocked coronary arteries with the hope of salvaging as much of the jeopardized heart muscle cells as possible. Unfortunately, despite advances over the past 2 decades, it is rarely possible to rescue the at-risk heart muscle cells from some degree of irreversible injury and death. Recently, it has been discovered that stem cells may hold therapeutic potential for these patients. Experimental studies in animals have revealed encouraging results when pluripotent stem cells are introduced into the heart around areas of myocardial infarction. These therapies appear to result in improvement in the contractile function of the heart. We propose to assemble a disease team focused on using cardiac progenitors derived from pluripotent cells to restore function in patients with ischemic cardiomyopathy. The proposed research will identify human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells that are best able to repair damaged heart muscle, thereby treating heart failure. Human ES and iPS cells grow and divide indefinitely while maintaining the potential to develop into many tissues of the body, including heart muscle. They provide an unprecedented opportunity to both study human heart muscle in culture in the laboratory, and advance the possibility of their use in therapy for damaged heart muscle. In addition to the health benefits to the people of California, and the anticipated savings in health care costs, these studies will lead to therapeutic technologies that could be used by the state and its biopharmaceutical industry to increase its tax base.
Review Summary: 
Executive Summary The proposal is to assemble a disease team focused on using cardiac progenitors derived from pluripotent cells to restore function in patients with ischemic cardiomyopathy. The proposed team plans to: 1) determine the optimal differentiation protocol(s), cell type(s), and progenitor stage for cell therapy; 2) refine integration, survival and electrical coupling of introduced cells; 3) perform preclinical studies; and 4) develop GMP quality cells. Regulatory and safety issues regarding clinical trials will also be addressed. The CIRM Disease Team planning grant will allow coordination of the community at two collaborating institutions, and potentially other locations. Reviewers felt that the proposed target is a plausible one, and one the researchers are well able to investigate. Ischemic cardiomyopathy is a major public health problem in the United States and, in its end-stages is unresponsive to drugs. Only modalities like biventricular pacing and eventually left-ventricular assist devices (LVADs) and transplantation are of benefit. Transplantation is a therapy in which supply is limited, and it is often complicated by rejection. Because in this clinical setting no one has identified an optimal stem cell for use, and because the stem cells presently used are safe but at best marginally effective, new approaches are needed. The approach proposed here is to be tackled by an impressive team and it is reasonable to expect that, if the plan stays on course, there will be entry to clinical trials by the end of a 5 year period. Reviewers concurred that the PI has an outstanding record of accomplishment, is head of a notable research group, and has long worked in the areas of genetic disease and developmental biology of the heart, and is well-funded in similar and complementary studies. The PI is the leader of the stem cell development program at the applicant institution, and has great experience in leading a research team and directing scientific programs. The PI’s experience in Phase 1 clinical trials is viewed as a strength. The planning process has been well thought out, and touches on all of the key points needed to take a basic science project to a clinical application. A group of basic, translational and clinical investigators are in place. The PI has also assembled an outstanding advisory board that includes expertise in basic and clinical research and in outreach to industry, to regulatory bodies and to industrial development. These components will all be brought together during the planning process to enable the group to compete effectively for a Disease Team Research Award. In summary, the panel was confident that this investigator could bring the project to fruition within the 5 year timeframe stipulated by the RFA. The well-conceived plan and the PI’s leadership skills were perceived as major strengths of the application. Reviewer Synopsis The proposal is to assemble a disease team focused on using cardiac progenitors derived from pluripotent cells to restore function in patients with ischemic cardiomyopathy. Some of the major approaches are: 1) Optimize directed differentiation of pluripotent cells and selection of cardiac progenitors. Develop more efficient methods to direct the differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells into relevant cardiac cell types and to select adequate numbers of cells. 2) Identify optimal cell type and progenitor stage for cell therapy. 3) Refine integration, survival, and electrical coupling of introduced cells. 4) Perform preclinical studies in large animals. 5) Develop GMP quality cells for therapy and conduct safe clinical trials. Regulatory and safety issues regarding clinical trials will also be addressed. The CIRM Disease Team planning grant will allow coordination of the community at Gladstone and UCSF, and potentially other locations. Reviewer One Comments Concept: The target is a plausible one, and one the investigators are well able to investigate. Ischemic cardiomyopathy is a major public health problem in the United States and, in its end-stages – is unresponsive to drugs. Only modalities like biventricular pacing and eventually LVADs and transplantation are of benefit. And this (transplantation) is a therapy in which supply is limited and which is often complicated by rejection. Because no one has identified an optimal stem cell for use here, and because the stem cells presently used are safe but at best marginally effective, new approaches are needed. The approach designed here is to be tackled by an impressive team and it is reasonable to expect that, if the plan stays on course, there will be entry to clinical trials by the end of a 5 year period. Principal Investigator: The PI has an outstanding record of accomplishment, is head of the Gladstone Institute, and has long worked in the areas of genetic disease and developmental biology of the heart. He is the leader of the stem cell development program at the Gladstone, and has great experience in leading a research team and directing scientific programs. Planning Approach: The planning process has been well thought out. A group of basic, translational and clinical investigators are in place. The PI has also assembled an outstanding advisory board that includes expertise in basic and clinical research and in outreach to industry, to regulatory bodies and to industrial development. These components will all be brought together during the planning process and it is highly likely that the group will compete effectively for a Disease Team Research Award. Reviewer Two Comments Concept: Concept/ Rationale. The authors propose to use stem cells to regenerate hearts. The objectives are to optimize differentiation of ES or iPS cells to cardiac progenitors, direct differentiation to relevant cardiac cell types. They also propose to identify which cell type is most relevant for this therapy, refine integration, survival, and correct electrical coupling. They propose large animal studies as preclinical models and finally propose a plan for large scale production of GMP grade cells for transplant. Maturity: This group already has substantial support from CIRM for similar studies to those proposed here, so the project may be mature but also is redundant. The final application will need to clearly details the new aspects of the proposed research. Significance. High Principal Investigator: Outstanding. Dr Srivastava is director of the Gladstone institute for Cardiovascular Disease (GICD), Professor of Pediatrics and Biochemistry and Biophysics, UCSF. He has considerable research support for similar and complimentary studies. He has experience in Phase 1 clinical trials. Planning Approach: The plan touches on all of the key points needed to take a basic science project to a clinical application. The way it is written the reader believes that the PI understands all of the potential problems and has addressed then when possible in the applications. One is confident that the project will be fruitful.
Conflicts: 

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