FDA-approved medications for heart failure patients after myocardial infarction consist of a multi-drug regimen. Patients with heart failure take these medications widely.
The clinical efficacies of each of these medications were tested in clinical trials that did not involve stem cell therapies. Due to the multiplicity of medicines, the choice of medicines for these multi-drug regimens is driven by cost considerations, patient/physician preference and/or tolerability issues.
Pre-clinical and epidemiological studies have demonstrated that some of this medicines have anti-growth and anti-inflammatory effects critical for cardiac recovery while others do not. More recently, some heart failure medications have been implicated in cancer suppression or progression. These processes are critical to the biology of stem cell transplantation and their use may be important in determining the benefit patients may gain from cell-based therapies. However, studies have not yet addressed the effects of heart failure medicines on stem cell biology. In this pre-clinical study, we propose that certain heart failure drugs may be beneficial for engraftment of transplanted stem cells and limit tumor production-a major limitation of translating stem cell therapies to the clinic.
Statement of Benefit to California:
In 2009, 259 Californians died per 100,000 due to heart disease. This translates into ~100,000 Californians dying per year despite access to standard of care therapies. This number of deaths from heart disease is greater than all cancer deaths in the same year. In addition, a 65-year-old patient who suffers a heart attack today has a 20% risk of subsequent hear failure and a 50% risk of death within 5 years. Disease progression occurs despite the use of current FDA-approved medical therapies and is attributable to a lack of heart regeneration along with continued cell loss. Cell-based therapies are being developed as a therapeutic approach that may substantially augment the current standard-of-care therapies. Such regenerative strategies are intended to restore lost myocardium in order to halt further clinical deterioration and improve depressed function. In this pre-clinical study, we propose that certain heart failure drugs may be beneficial for engraftment of transplanted stem cells and limit tumor production-a major limitation of translating stem cell therapies to the clinic. If already FDA-approved drugs that are available in generic forms are helpful to stem cell engraftment, Californians will not have to pay the cost of developing NEW drugs which will drive the cost of health care up. Instead, we propose using already available drugs first if they prove to help stem cell engraftment without toxicity.
The goal of this proposal is to assess FDA-approved heart failure medications for their potential effect on the success of cell-based cardiac therapy following a heart attack. The premise behind this proposal is that even if cardiac cell therapies are used in the future for treatment of heart failure, it is likely that patients will concomitantly receive one or more of the current standard heart failure medications, some of which may enhance the success of the transplant and some of which may inhibit it. This study aims to provide data that will help guide the choice of such medications to use in conjunction with a cell transplant. To achieve this goal, the applicant will first do in vitro studies to identify approved heart failure medications that have a pro-survival effect on cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) (Aim 1). Next the applicant will test the effect of those drugs on survival and engraftment of hiPSC-derived cardiomyocytes in a mouse model of myocardial infarction (Aim 2). Finally, the mouse model will be used for a placebo-controlled preclinical study to directly compare regimens identified (Aim 3).
- The concept behind this proposal is premature, since the optimal cell type for cell-based cardiac therapy is not yet identified and therefore it is unknown what cell type to evaluate in these experiments.
- The significance of the proposal is hard to evaluate since there is no data as to whether any heart failure medications affect stem cell therapy.
- The scientific rationale for and value of using the murine system to study human cardiomyocyte engraftment in heart failure is unclear since it is very difficult to mimic heart failure in a mouse. Furthermore, the use of immune-deficient mice is not a realistic model of the ultimate goal of transplantation into immune-competent patients.
- The feasibility of achieving the stated goals was questioned given the poor efficiency of cardiomyocyte differentiation reported in the preliminary data; this efficiency was far below what has been routinely achieved by others.
- Although experienced in the surgery necessary for cell transplantation, the PI lacks the expertise to efficiently differentiate cardiomyocytes from iPSC.
- The publication record for the PI includes few relevant publications, and the PI has only a single publication as a first author in a significant (although specialized) journal.
- Reviewers were skeptical as to whether the mentors chosen had the necessary expertise to provide guidance for this proposal.
- Institutional commitment to the PI appears to be moderate. Although laboratory space was provided, startup funds were not impressive.
- The PI’s faculty status and particularly, the issue of whether the applicant is in a tenure-track position, was not clear and of concern to reviewers.
- The PI’s institution is clearly committed to translational stem cell research.
- The proposal is responsive to the RFA in that it uses human stem cells, the research is translational and the research is unlikely to receive federal funding.