For the millions of Americans who are born with or develop heart disease, stem cell research offers the first hope of reversing or repairing heart muscle damage. Thus, early reports suggesting heart regeneration after transplantation of adult bone marrow-derived stem cells were met with great excitement in both the scientific and lay community. However, although adult stem cell transplantation was shown to be safe, results from over a dozen clinical trials concluded that the benefits were modest at best and whether any true regeneration is occurring was questionable. The basis for these disappointing results may be related to poorly characterized cell types used that have little capacity for true regeneration and an inadequate understanding the factors necessary for survival and differentiation of transplanted stem cells. In this application, we are proposing to develop a cardiac cell therapy using cardiac progenitor cell, which is isolated from human induced pluripotent cells that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We will develop the techniques and models that will allow the preclinical testing of this progenitor cell, which is required by the FDA to move to clinical trials. This knowledge will be applied to future clinical trials of cardiovascular cell therapy that allow truly regenerative therapy.
Statement of Benefit to California:
Heart disease, stroke and other cardiovascular diseases are the #1 killer in California. Despite medical advances, heart disease remains a leading cause of disability and death. Recent estimates of its cost to the U.S. healthcare system amounts to almost $300 billion dollars. Although current therapies slow the progression of heart disease, there are few, if any options, to reverse or repair damage. Thus, regenerative therapies that restore normal heart function would have an enormous societal and financial impact not only on Californians, but the U.S. more generally. The research that is proposed in this application could lead to new therapies that would restore heart function after and heart attack and prevent the development of heart failure and death. We will develop the techniques and models that will allow the testing of this progenitor cell as required by the FDA to move to clinical trials.
This development candidate feasibility proposal aims to test the efficacy of autologous induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPC) as a regenerative therapy to treat myocardial infarction (MI), or heart attack. The applicants plan to adapt their current research grade iPSC-CPC generation procedure to good manufacturing practice (GMP)-compatible production methods. They will then test the cells for their ability to improve cardiac function in both xenograft and autologous preclinical cardiac infarction models.
Reviewers supported the theoretical rationale behind the proposed project. The cell loss and adverse remodeling that follows MI can progress to heart failure. Heart transplant offers the only curative treatment for this fatal condition, yet donor hearts are limited and patients require lifelong immunosuppression. If successfully developed, an autologous, regenerative therapy for MI that stabilizes or restores cardiac function would have a profound clinical impact. The potential for iPSC-CPC to form endothelial cells, smooth muscle cells and cardiac myocytes may offer an important therapeutic advantage over other cell sources. However, reviewers noted a potential flaw in the rationale for developing an iPSC-based therapy. If treatment must occur shortly after injury to achieve efficacy, there may be insufficient time to reprogram and differentiate the patient’s cells. Such a scenario would obviate the possibility of using autologous iPSC-CPC and necessitate the use of a donor cell source with immunosuppression.
Reviewers agreed that the preliminary data substantiating the applicants’ ability to generate iPSC-CPC forms a solid foundation for the proposed approach. They also appreciated the logical plan for iPSC-CPC development. However, the lack of convincing data that even research grade iPSC-CPC could improve cardiac function post infarct was a critical weakness of this proposal. Given evidence from the literature that transplantation of multiple cell types, including cardiac myocytes, is of only limited benefit, reviewers felt the translational potential of iPSC-CPC was inadequately justified. The panel strongly advised that the applicants first optimize conditions to demonstrate cardiac functional benefit of iPSC-CPC in a small animal model prior to proceeding with the selected preclinical model and the proposed extensive efforts to scale up and adapt the iPSC-CPC process to GMP. Reviewers also expressed hesitation regarding the feasibility of the proposal, noting a general dearth of alternative plans. They found the proposed efforts to adapt the current labor-intensive, research grade iPSC-CPC process to GMP compatible methods overly broad in scope and unlikely to be completed in the award period. In particular, reviewers found the screen for factors that regulate CPCs in dual culture systems complex, exploratory in nature and poorly described. Finally, while reviewers appreciated the applicants’ ability to perform autologous testing of iPSC-CPC in a relevant preclinical model, it was unclear that these cells would reflect the behavior of human iPSC-CPC. Taken together, these issues led reviewers to conclude that the program was not yet sufficiently mature for a translational effort.
The PI is well qualified to lead this program and has assembled a team with appropriate experience to perform the proposed studies. Reviewers noted expertise with iPSC generation in the selected model and successful IND filings as strengths of the team. Given the complexity of the proposed work, they expressed concern that the investigators’ level of commitment would prove insufficient to ensure success of the program. A more detailed communication plan and inclusion of a GMP expert would benefit the proposal. The PI’s institution possesses superb facilities but institutional support is unclear.
This proposal to develop iPSC-CPC as a therapy for MI was not considered sufficiently mature for a translational effort. An established body of literature suggests that transplantation of multiple cell types, including cardiac myocytes, provides only limited improvement in cardiac function. In this context, the lack of convincing in vivo functional data with iPSC-CPC comprised a critical flaw and the grants working group recommended against funding the application.