New Faculty Physician Scientist
$3 004 315
Despite therapeutic advances, cardiovascular disease remains a leading cause of mortality and morbidity in California. Regenerative therapies that restore normal function after a heart attack would have an enormous societal and financial impact. Although very promising, regenerative cardiac cell therapy faces a number of challenges and technological hurdles. Human induced pluripotent stem cells (hiPSC) allow the potential to deliver patient specific, well-defined cardiac progenitor cells (CPC) for regenerative clinical therapies. We propose to translate recent advances in our lab into the development of a novel, well-defined hiPSC-derived CPC therapy. All protocols will be based on clinical-grade, FDA-approvable, animal product-free methods to facilitate preclinical testing in a large animal model. This application will attempt to translate these findings by: -Developing techniques and protocols utilizing human induced pluripotent stem cell-derived cardiac progenitor cells at yields adequate to conduct preclinical large animal studies. -Validation of therapeutic activity will be in small and large animal models of ischemic heart disease by demonstrating effectiveness of hiPSC-derived CPCs in regenerating damaged myocardium post myocardial infarction in small and large animal models. This developmental candidate and techniques described here, if shown to be a feasible alternative to current approaches, would offer a novel approach to the treatment of ischemic heart disease.
Statement of Benefit to California:
Cardiovascular disease remains the leading cause of morbidity and mortality in California and the US costing the healthcare system greater than 300 billion dollars a year. Although current therapies slow progression of heart disease, there are few options to reverse or repair the damaged heart. The limited ability of the heart to regenerate following a heart attack results in loss of function and heart failure. Human clinical trials testing the efficacy of adult stem cell therapy to restore mechanical function after a heart attack, although promising, have had variable results with modest improvements. The discovery of human induced pluripotent stem cells offers a potentially unlimited renewable source for patient specific cardiac progenitor cells. However, practical application of pluripotent stem cells or their derivatives face a number of challenges and technological hurdles. We have demonstrated that cardiac progenitor cells, which are capable of differentiating into all cardiovascular cell types, are present during normal fetal development and can be isolated from human induced pluripotent stem cells. We propose to translate these findings into a large animal pre-clinical model and eventually to human clinical trials. This could lead to new therapies that would restore heart function after a heart attack preventing heart failure and death. This will have tremendous societal and financial benefits to patients in California and the US in treating heart failure.
Executive Summary The focus of this proposal is to develop a regenerative therapy based on cardiac progenitor cells (CPCs) that engraft and regenerate damaged myocardium after a heart attack, thereby preventing the progression to heart failure. Toward that goal, the applicant will first develop a method to derive high purity human CPCs from induced pluripotent stem cells (iPSC) under clinically compatible conditions and in sufficient numbers for potential use as a therapeutic (Aim 1). These cells will then be transplanted into immunodeficient animal models of myocardial infarction in order to test their ability to regenerate heart tissue and restore function (Aim 2). Research Plan - The proposed therapy would have a highly significant impact if it successfully prevents the progression from heart attack to heart failure. There is an unmet need among heart failure patients, for whom prognosis is poor and the only curative treatment is heart transplant. - The applicant’s use of an immunodeficient, relevant preclinical model generated enthusiasm and the ensuing data will inform the field. - The preliminary data presented supports the approach and the rationale is logical and compelling. - There are some risks to the plan, including the facts that it is very challenging to expand CPC, and that there are lots of competitors in this area. In addition, it was not clear what GMP expertise would be available to the project. Principal Investigator - The PI has a good track record in the field and is already involved in a stem cell clinical trial as part of his/her clinical work. However, reviewers noted the PI’s modest publication record to date. - The PI has had the vision to assemble an appropriate team to help move this approach toward a cardiac therapy. - The PI has selected appropriate mentors with the necessary expertise and qualifications to guide his/her career development. - A major strength of the career development plan is the close link between the clinical and investigative components of the PI’s work. - It was suggested that developing career milestones in the mentoring plan would be useful. Institutional Commitment - The institution has made a substantial commitment to the PIs research career in providing 80% protected research time, adequate laboratory space, research support and mentoring. - The technology platforms and core facilities available to the candidate are impressive. - The institution has a strong track record of developing investigative faculty. Responsiveness - The proposal is responsive to the RFA in the use of human iPSC, the development of expansion and selection protocols to purify the cells of interest, and in the use of a relevant preclinical model.