Heart disease is the number one cause of morbidity and mortality in the US. With an estimated 1.5 million new or recurrent myocardial infarctions, the total economic burden on our health care system is enormous. Although conventional pharmacotherapy and surgical interventions often improve cardiac function and quality of life, many patients continue to develop refractory symptoms. Thus, the development of new therapies is urgently needed. “Tissue engineering” can be broadly defined as the application of novel bioengineering methods to understand complex structure-function relationships in normal or pathological conditions and the development of biological substitutes to restore, maintain, or improve function. It is different from “cell therapy”, which is designed to improve the function of an injured tissue by simply injecting suspensions of isolated cells into the injury site. To date, two main limitations of cell therapy are (1) acute donor cell death due to unfavorable seeding environment and (2) the lack of suitable cell type that genuinely resembles human cardiac cells. Our proposal seeks to use engineered tissue patches seeded with human embryonic stem cell-derived cardiomyocytes for treatment of ischemic heart disease in small and large animal models. It represents a significant development of novel techniques to address both of the main limitations of cell therapy, and will provide a new catalyst for the entire field of stem cell-based tissue engineering.
Patients with end-stage heart failure have a 2-year survival rate of 25% by conventional medical therapy. Not commonly known to the public is that this dismal survival rate is actually worse when compared to patients with AIDS, liver cirrhosis, or stroke. Following a heart failure, the endogenous repair process is not sufficient to compensate for cardiomyocyte death. Thus, novel therapies with stem cells in combination with supportive scaffolds to form engineered cardiac tissue grafts is emerging as a promising therapeutic avenue. Engineered tissues have now been used to make new bladders for patients needing cystoplasty, bioarticial heart patches seeded with bone marrow cells, and more recently new trachea for patient with late stage tracheal cancer. Our multi-disciplinary team intends to push the therapeutic envelop by developing human tissue engineered myocardium for treatment of post-myocardial infarction heart failure. We will first test our engineered cardiac tissue in small and large animal models. We will perform extensive quality control measures to define morphological, molecular, and functional properties. At the end of 3 years, we are confident we will be able to derive a lead candidate that can move into IND-enabling preclinical development. These discoveries will benefit the millions of patients with heart failure in California and globally.
This development candidate (DC) proposal aims to evaluate an engineered heart tissue (EHT), containing human embryonic stem cell derived cardiac myocytes (hESC-CM), in preclinical models of end stage heart failure. Given that the majority of cells injected into the heart are rapidly lost, the applicants hypothesize that retaining cells using this patch-based approach will improve engraftment and heart function. The preclinical models will be assessed for cardiac function, graft retention, graft integration and safety. Additionally, the applicants will develop scaled up GMP compatible production methods, shipping standard operating procedures (SOPs), and assays to characterize materials before and after shipping. The proposal represents an international collaborative effort between individuals with expertise in stem cells, cardiac imaging, tissue engineering and cardiac surgery.
Objective and Milestones
- The objective and milestones are feasible, well planned and appropriately focused to accomplish a complex DC.
- The target product profile is scientifically reasonable and drives toward a first-in-human study to assess safety, appropriate for this stage of research. Reviewers recommended that the applicants consider into which patient population the team would advance the therapeutic candidate.
Rationale and Significance
- If successfully developed, the proposed DC could address a huge unmet clinical need in end stage heart failure, for which the prognosis is poor and treatment options are limited.
- The panel appreciated that the EHT approach addresses the rapid loss of transplanted cells, a bottleneck in development of cell therapies for the heart.
- If successfully developed, this DC will demonstrate feasibility of repairing a complex organ with an hESC-based tissue engineering strategy.
Research Project Feasibility and Design
- Reviewers were highly enthusiastic about the proposed program. The plan is logical and well-designed, and addresses all required elements to achieve a DC ready for IND-enabling studies.
- While the manufacturing and in vivo testing required to achieve this DC are technically demanding, compelling preliminary data and team expertise gave reviewers confidence that the team could successfully execute the proposed program.
- Reviewers discussed the immunological challenges of xenotransplantation in the large animal model. They strongly advised the applicants to begin in vitro testing of the selected immunosuppression regimen to ensure similar activity in both preclinical models early in the program.
- Potential immunogenicity of the DC should also be assessed.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The panel expressed universal enthusiasm regarding the qualifications of the PI, Co-PI, Partner PI and the other members of the first rate, collaborative team.
- The budget is appropriate to support the proposed studies.
Collaborations, Assets, Resources and Environment
- Collaborations are critical to the success of the program, and reviewers valued the established collaboration with the Partner PI.
- Resources at the host institution are excellent for translational studies, including facilities and expertise for the proposed in vitro studies.
Responsiveness to the RFA
- The proposal describes a novel development candidate derived from pluripotent human cells, rendering it highly responsive to the RFA.