Overcoming the Translational Challenges of Using Pluripotent Stem Cells for Therapy in an Ischemic Cardiomyopathy Model
Early Translational I
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 developed methods for identifying and isolating specific types of hESCs, stimulating them to become human heart muscle cells, delivering these into the hearts of mice after heart attack, and assessing their functional benefits. However, to advance this therapy to human patients, studies must be carried out in large animal models that closely mimic the human disease, and a number of major bottlenecks must be overcome. In this proposal, we will use a model of heart attack in the pig that closely resembles the human disease to address these bottlenecks. We will evaluate how the recipient animal’s immune system responds to hESC therapy and develop ways to modulate this response; develop methods to increase the local retention and survival of hESC cells after delivery into the heart; and assess the safety hESC therapy with regard to heart function, rhythm and tumor formation. These studies also are designed to 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 developed methods for identifying and isolating specific types of human embryonic stem cells (hESCs), stimulating them to become human heart muscle cells, delivering these into the hearts of rodents after myocardial infarction, and assessing their retention and ability to couple electrically and functionally to the myocardium. The current proposal will move our group’s accomplishments forward in a large animal (porcine) pre-clinical model designed to address translational bottleneck issues. To this end, we have assembled a multidisciplinary team of seasoned co-investigators and consultants, including basic scientists, biomedical engineers, cardiologists, immunologists, pathologists, electrophysiologists, and human clinical trials experts to successfully address the Aims in this proposal, and pave the way for advancing this novel therapy to patients. Even though we propose to use an ischemic cardiomyopathy model of heart failure as a way to address the bottleneck issues relevant to hESC therapy for human disease, we fully expect our research to generate solutions that could be applicable to the development of therapies for other human diseases characterized by organ damage or insufficiency. 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 and better prepare us to utilize these funds when they become available in the future.
This proposal addresses several bottlenecks in the translation of cardiac stem cell therapies for heart failure. The applicant proposes to develop methods for differentiation and selection of human embryonic stem cell (hESC)-derived myocardial precursor cells (hEMPs), to improve yield and purity of these precursors while minimizing the risk of teratoma formation. The investigators will then test these hEMPs in a preclinical model of myocardial infarction (MI), monitor immune responses and evaluate two immunosuppressive regimens. The second aim of the proposal describes the development and evaluation of a synthetic extracellular matrix (ECM) to improve the retention and function of transplanted hEMPs. In the third and final aim the applicant proposes to assess the safety of hESC therapy in the preclinical model using optical mapping and Holter monitoring. The reviewers agreed that this proposal a ddresses several significant bottlenecks and could therefore have a major impact on the field. They appreciated that experience gained in the use of the proposed preclinical models and the evaluation of immune responses to cell transplants are important steps toward clinical trials. However, one reviewer expressed serious concerns about the xenogeneic transplantation model. This reviewer stressed the high barriers to immune suppression in xenogeneic models and cautioned that it may not be possible to achieve long-term survival and function of hEMPs in the proposed preclinical model. Overall this reviewer felt that many of the proposed experiments, including those involving cell selection, teratoma formation and safety issues, should be fully addressed (to the extent possible) in immunodeficient mouse models prior to performing them in the proposed preclinical model. The reviewers found the proposal’s specific aims to be carefully designed and logically described. One reviewer praised the success criteria and discussion of potential difficulties as well as alternative approaches. However, there were some questions about the feasibility of the research plan. One reviewer felt that Aims 1 and 3 were strong but that Aim 2 lacked sufficient detail. This reviewer cautioned that the development of an optimal hEMP-specific synthetic ECM is not a trivial undertaking. hESCs versus more differentiated cells have different affinities for binding the proposed peptide, and optimization may not be straightforward. Further, too little information was provided about Aim 2 to inspire confidence in the likelihood of success. Another reviewer commented that the lack of preliminary data from studies of hEMP transplantation into immunodeficient mice was a weakness and made it difficult to judge the project’s feasibility. This reviewer also noted that, in the immune response studies, antibodies will be examined in the graft but not in the plasma, and that the other proposed immune response studies were not likely to detect all the important immune responses. Another reviewer strongly suggested the addition of a fifth study group to the immunosuppression studies: a group receiving immunosuppression without cell therapy. In light of increasing evidence about the importance of inflammation in the evolution of coronary artery disease, it would be important to examine the impact of immunosuppression alone as a concurrent control in this experiment. The reviewers agreed that the applicant is an accomplished cell biologist-physician scientist and team leader, and has assembled a highly qualified research team. They noted that the team has experience working together effectively and their resources and research environment are outstanding. One reviewer commented that the overall number of personnel was quite large and seemed excessive for the work proposed. Another reviewer felt that the research team lacks sufficient experience with xenotransplantation. The budget was deemed generally appropriate but one reviewer felt that insufficient resources were devoted to Aim 2. This reviewer did not feel that the subcontract budget of ~$90,000/year would be adequate to develop and evaluate a novel synthetic ECM for hEMPs. Overall the reviewers found this to be a sophisticated proposal addressing a number of important translational bottlenecks. However, they raised significant concerns about the feasibility of the research plan, specifically in the areas of immune suppression in xenotransplantation models and development of a synthetic ECM for hEMPs.