Early Translational II
$1 753 057
Five million people in the United States suffer with heart failure, resulting in ~60,000 deaths at a cost of $30 billion/year. These patients also are more prone to sudden cardiac death, causing ~500,000 deaths annually. In addition, ~80,000 children are born each year in the United States with congenital heart disease, the most common human birth defect, and many of these children eventually develop heart failure. 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. Despite advances over the past two decades, it is rarely possible to rescue heart muscle from some degree of irreversible injury and death after a heart attack, and none of the currently accepted therapies replace damaged heart muscle with new heart cells. Human embryonic stem cells (hESCs) 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 advance new cell-based therapies for heart attack and heart failure. We have identified a human stem cell that gives rise to many of the types of muscle cells in the heart. In this proposal, we will test whether this cell can be used to repair damaged heart muscle in a heart attack model in the pig that closely resembles the human disease. We will develop methods to increase the local retention and survival of these cells after delivery into the heart; determine ways to prevent the body from rejecting these cells; and assess the safety of these cells with regard to heart function, rhythm and tumor formation. These studies may also generate solutions that will allow us to bring hESC therapy not only to heart attack victims, but to those bearing the burden of other diseases where organs are damaged or not functioning properly.
Statement of Benefit to California:
Heart failure is very common with ~100,000 people in California suffering from this condition at a cost of ~$540 million/year. In addition, ~11,000 children are born in California each year with congenital heart disease, the most common human birth defect. Many will develop heart failure at an additional cost of ~$75 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 repair itself. Our group has identified a human stem cell that gives rise to many of the types of muscle cells in the heart. The current proposal will move our group’s accomplishments forward by testing whether this cell can be used to repair damaged heart muscle in a heart attack model in the pig that closely resembles the human disease. To this end, we have assembled a multidisciplinary team of seasoned co-investigators, including cell biologists, immunologists, biomedical engineers, cardiologists, and electrophysiologists, to successfully address the Aims in this proposal, and pave the way for advancing this novel therapy to patients. 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. This research also will push the field of regenerative medicine forward despite the paucity of federal funds for early translational research.
This development candidate feasibility (DCF) proposal aims to test the therapeutic potential of human embryonic stem cell-derived myocardial progenitors (hESC-MP) for ischemic cardiomyopathy. Investigators proposed to develop a biomimetic peptide-polymer carrier to be transplanted with hESC-MP cells in order to facilitate cardiac engraftment. They will also study the immune response to the preparation and explore immunosuppression regimens to enable graft retention in immunocompetent large animal models. The cell preparation will then be assessed for safety as well as cardiac functional benefit in a relevant preclinical model of ischemic heart disease. The cell loss and adverse remodeling following myocardial infarction can ultimately result in heart failure. Heart transplant provides the only curative treatment for this fatal condition, and donor hearts are limited. Therefore, reviewers appreciated the applicant’s rationale to replace lost cardiac myocytes and they found the approach to use a defined peptide for the support of transplanted hESC-MP to be a strength of the proposal. If successful, this approach would have a major impact. The preliminary data shows that the applicant can generate hESC-MP and provides solid support for the use of the synthetic peptide as a matrix for hESC-MP differentiation. However, the reviewers emphasized that the field is relatively mature. Previous studies in cardiac regeneration demonstrate only limited benefit from transplantation of various cell types, including hESC-derived cardiac myocytes (hESC-CM). The applicant hypothesizes that the less mature hESC-MP will engraft better than hESC-CM, but provides no supporting data. Further, the panel emphasized that engraftment of cells does not ensure improved cardiac function. Therefore, reviewers felt strongly that improved efficacy of hMPs in a disease model must first be demonstrated to justify further effort with this cell type, and the absence of such data was considered a critical flaw. The rest of the plan, including the histology, immunology and electrical integration studies, was deemed feasible. The principal investigator (PI) has an excellent track record in both hESC and cardiac progenitors and has assembled an appropriate and very strong team. Reviewers appreciated that collaborations among team members are already ongoing. They differed in their opinion regarding commitment to the proposed project. While some felt that levels of commitment are adequate, others expressed concern that efforts by an important co-investigator would not be sufficient to support this complex project. The stem cell facilities, environment and support of the applicant institution are excellent. Overall, this proposal had some positive aspects including an excellent PI, team and convincing data that the group can generate the target cells. However, given the limited benefit published with a very closely related cell type and the absence of presented evidence that the proposed DC is superior, reviewers were unenthusiastic about the therapeutic potential and impact and did not recommend the application for funding.