Early Translational I
$4 512 794
The goal of this project is to develop a cell-based treatment for heart disease that will increase blood flow to the heart and repair damaged heart tissue by directly adding new cardiac cells to the heart muscle wall. This therapy is intended to restore the pumping function of the heart and reverse the symptoms of Heart Failure by treating the underlying causes of the disease. Our proposed technology is based upon two existing components, each of which contains a different population of human cells. The first component is an engineered human tissue patch that is FDA-approved for wound healing and is currently being evaluated in human clinical trials in the United States for the treatment of heart disease. Formation of new mature blood vessels and healing of damaged and ischemic tissues in response to the patch has been demonstrated in animals and humans. The second component is a highly purified population of FDA-compliant human embryonic stem cell-derived cardiac progenitor cells generated in a certified GMP facility. These cardiac progenitor cells can form beating cardiac tissue in vitro when permitted to mature, and are capable of replacing lost or damaged heart muscle. We plan to test whether these cells are also capable of integrating with a patient’s cardiac tissue after implantation, and whether this can improve global heart function. We will evaluate whether the combination of the tissue patch and the cardiac progenitor cells can address certain limitations of cardiac cell therapy. If successful, we hope to demonstrate several advantages. First, that the tissue patch may provide a means for reliable and reproducible delivery of these “myocardial replacement” cells to the heart. Second, that delivery via a patch can enhance survival of these cells in a patient’s damaged heart tissue, as well as promote successful engraftment into the heart. Third, that better control over the delivery of the cardiac progenitor cells may be achieved using a patch methodology versus infusion or injection, which could reduce or eliminate ectopic node formation. And finally, that establishment of a viable culture of cardiac progenitor cells in the patch prior to implantation could allow a controlled dose of these cells to be delivered to the heart in a site-specific manner. Successful completion of this project will advance our proposed therapeutic technology to IND-enabling pre-clinical studies in three years.
Statement of Benefit to California:
In the United States, Heart Failure (HF) results in more deaths than cancer, accidents, and strokes combined, costing more than $35 billion annually. It is estimated that in the United States, 5,300,000 patients have HF, with an additional 550,000 new cases per year. Cardiovascular disease is the leading cause of death in California where there are annually about 575,000 heart disease-related hospital discharges and 350,000 of these are for HF. The vast majority of patients who develop Heart Failure in the US do so after myocardial infarction (MI). According to the American Heart Association, approximately 22 percent of male and 46 percent of female MI victims will be disabled with HF within six years. The annual incidence of MI in the United States is 600,000 for first a first attack and 320,000 for recurrent attacks. Once a patient becomes symptomatic with HF, the prognosis is worse than many forms of cancer. A patient with symptomatic HF has a mortality rate approaching 50% in five years. HF is a progressive disease, which ultimately leads to death. Current therapies temporarily relieve symptoms, but there is no cure. The only treatment for the most advanced cases is a heart transplant, which is not a feasible option for most patients. The need for donor organs for the sickest patients far exceeds the number available. Cell replacement therapy is a more practical alternative, but there is currently an insufficient supply of appropriate cells for cardiac muscle replacement. Human embryonic stem cells can address this need, as they are unlimited in proliferative capacity and are capable of differentiating into cardiac cells for heart muscle repair. New therapeutics targeting the progression of HF will make a significant economic impact in the United States and in California. Successful development of a therapeutic that can treat or reverse Heart Failure will result in cost reductions in the care of cardiovascular disease, and an increase in productivity and quality of life for a large sector of the population. We hope to demonstrate that our proposed cell-therapy product will halt the progression of HF or even reverse the deleterious effects of HF on the patient's heart. By restoring the pumping ability of the heart, this product, if successful, will help the HF patient to lead a more normal, active life. Successful development of this product will contribute to the broader goal of advancing stem cell-derived therapeutics through the clinical and regulatory process and will help pave the way for other stem cell-derived therapies to improve public health.
Congestive heart failure is a devastating condition in the United States and worldwide, and existing therapies, ranging from drugs through transplant, are inadequate to solve the problem. This application focuses on developing a therapy for congestive heart failure (CHF) complicating myocardial infarction. Specifically, the application proposes a myocardial repair patch (MRP) that is designed to treat heart failure by restoring perfusion in ischemic cardiac tissue and performing tissue repair by replacement/augmentation of damaged myocardium. This MRP incorporates a 3D fibroblast construct (3DFC) currently in use in the US for wound healing and a high purity population of human embryonic stem cell (hESC)-derived cardiac progenitor cells as an off-the-shelf allogeneic therapy. The 3DFC already has been shown to be safe and effective in promoting wound healing and to promote angiogenesis in this setting. The proposed therapy is targeted specifically at patients with moderate to severe CHF undergoing a coronary artery bypass graft (CABG) procedure. Strong supportive evidence exists that 3DFCs are effective in a wound healing setting and hESC-derived cells may be advantageous in cardiac regenerative therapies. With this background, reviewers believed the application addressed an important, unmet clinical need; however, significant potential limitations exist for patch-based methods of myocardial repair, including the ability of patches to deliver significant improvements in cardiac hemodynamics in hearts that have sustained long-term, diffuse damage. This potential issue was not adequately addressed within the proposal. The reviewers also believed that other critical issues needed to be addressed with the research plan. A major weakness of this application is that it proposes work outside of the scope of the RFA; the application was not responsive to the RFA. Primarily, the focus on manufacturing and scale-up issues is outside the focus of this RFA. In addition, though numerous safety issues surround clinical application of hESCs, the applicant made no mention of contact with the FDA to receive guidance on executing the early stages of this study. Genetic and epigenetic changes in hESC culture and undifferentiated hESCs in patches must be screened using more than Oct4 immunochemistry, and a strategy more sensitive and sophisticated than immunostaining was not presented. The proposal offered some preliminary data concerning the 3DCFC patch and some evidence that cardiac progenitors and fibroblasts could be co-cultured in the patch, which was encouraging. However, the proposed research plan was poorly described and lacked sufficient detail for a project of this magnitude, and so it is difficult to judge the feasibility or appropriateness of the timelines. No potential limitations or alternative approaches were presented, and these gaps greatly diminished enthusiasm for the proposal. The applicant also takes shortcuts in interpretation that are not reflected in the reality of the experimental setting. For example, the discussion of immunosuppression in the human setting was imprecise; interpretation of what a positive connexin43 stains revealed about the functionality of the construct-native environment interaction was flawed; and the 3DFC canine studies lacked compelling preliminary data. In addition, significant budgetary concerns raised serious concerns about the likelihood for successful management and completion of the stated aims. The qualifications of the applicant and research team are excellent in cardiology and stem cell biology. However, a number of them have expertise in manufacturing which may be premature in an early stage translational RFA. One reviewer expressed concern regarding the large size of the team, and perhaps, that the team and budget were overinflated given the scope of the proposed work. Reviewers felt that the scientific aims could be achieved more efficiently with a slightly greater percent effort commitment by a few personnel and the reduction/removal of others. The proposal requests a significant amount of equipment for GMP compliance. However, some or all of these expenses could/should be assumed by the applicant company and are actually potentially underestimated depending upon the numbers and quality of the individual equipment items listed. In summary, this project seeks to create a MRP composed of a 3DFC and a highly purified population of hESC-derived cardiac progenitor cells. This approach addresses an important unmet clinical need in developing a therapy for CHF; however; glaring limitations exist in this proposal regarding experimental design, safety issues, budgetary concerns, and a dearth of preliminary data that greatly diminish the likelihood for successful management of the research program and completion of the stated aims.