Patients with end-stage heart failure (ESHF) have a 2-year survival rate of 50% with conventional medical therapy. This dismal survival rate is actually significantly worse than patients with AIDS, liver cirrhosis, stroke, and other debilitating diseases. Stem cell therapy may be a promising strategy for inducing myocardial regeneration via paracrine activation, prevention of cardiac apoptosis, and other mechanisms. Several studies have convincingly shown that human embryonic stem cells can be differentiated into cardiomyocytes (hESC-CMs) and that these cells can be used to effectively improve cardiac function following myocardial infarction (MI). The objectives of this CIRM Disease Team Therapy proposal are two-fold: (1) to perform IND enabling studies involving hESC-CM for subsequent FDA approval and (2) to complete a Phase I trial with ESHF patients undergoing the left ventricular assist device (LVAD) procedure whereby hESC-CMs will be injected at the same time.
Coronary artery disease (CAD) is the number one cause of mortality and morbidity in the US. Following myocardial infarction (MI), the limited ability of the surviving cardiac cells to proliferate thereafter renders the damaged heart susceptible to dangerous consequences such as heart failure. In recent years, stem cell therapy has emerged as a promising candidate for treating ischemic heart disease. In contrast to adult stem cells, human embryonic stem cells (hESCs) have the advantage of being pluripotent, which endows them with the ability to differentiate into virtually every cell type. Numerous studies have demonstrated that hESC-derived cardiomyocytes (hESC-CMs) can improve cardiac function in small and large animal models. In addition, the FDA has approved hESC-derived oligodendrocyte progenitor cells for patients with acute spinal cord injury and hESC-derived retinal pigment epithelial cells for patients with Stargardt’s macular dystrophy. Hence the conventional controversies and regulatory hurdles related to hESC-based trials are no longer major barriers to the field. In this proposal, we seek to extend and translate the robust pre-clinical data into clinical reality by demonstrating the safety and feasibility of hESC-CM transplantation. We will perform careful IND-enabling research in the first 3 years. Afterwards, our medical teams will initiate a phase 1 clinical trial involving 10 patients with end stage heart failure (ESHF). We will perform direct intramyocardial injection of hESC-CMs in ESHF patients undergoing left ventricular assist device (LVAD) implantation as a bridge toward orthotopic heart transplantation (OHT). After the patients have received matching donor hearts, the native recipient hearts will be explanted. This will provide us an opportunity to carefully assess the fate of these cells and to ensure safety before we can embark on a larger clinical trial in Years 5-10.
This proposal aims to develop human embryonic stem cell derived cardiac myocytes (hESC-CM) for the treatment of end stage heart failure through investigational new drug (IND)-enabling studies and completion of a phase I clinical trial. The applicants propose to optimize differentiation to hESC-CM, develop assays, perform process development and manufacturing, optimize dosing, develop immunosuppression protocols and perform IND-enabling safety and efficacy studies in years 1-3. After submission of an IND in year 4, the applicants plan to initiate a phase I clinical trial. In the trial, hESC-CM will be injected in to the heart following placement of a left ventricular assist device (LVAD), which is a bridging treatment pending a heart transplant. In addition to assessing safety in man, engraftment of hESC-CM in the recipient patients’ hearts will be examined following heart transplantation.
Significance and Impact
- Heart failure presents a clear unmet medical need for which treatment options are limited.
- Reviewers were very enthusiastic regarding the potential power of this study to inform the field. If successful, the work could reveal the fate of transplanted allogeneic hESC-CM in human hearts and whether they are able to functionally engraft following injection and inform future development of this approach.
- Questions were raised regarding remodeling of the heart caused by LVAD-induced unloading which may affect cell integration and resulting conclusions that can be drawn.
Project Rationale and Feasibility
-The target product profile describes a reasonable target product and the plan addresses the necessary elements to achieve an IND filing. The application presents a clear clinical scenario.
- The panel also appreciated the concept of injecting hESC-CM into LVAD “unloaded hearts” and felt this approach could improve both cardiac engraftment and reduce off-target delivery.
- Preliminary data demonstrate disease-modifying activity of injected hESC-CM in preclinical models of heart disease, providing robust support for the proposed approach. However, the mechanism of action for this therapy remains unclear.
- Reviewers highlighted the program’s early stage of development: the plan lists two potential parent hESC lines to generate hESC-CM, the differentiation method remains to be optimized, and the production process is not yet locked down. The application lacks clear scale up plans.
- Potential intellectual property issues could result from use of one of the proposed parental hESC lines.
- The group cautioned the team will need very sensitive assays to detect potential residual hESC in their lots and that the FDA may require longer duration safety studies to address teratoma risk.
- A panelist also noted this project predominantly addresses safety rather than efficacy. S/he wondered what mechanistic data might be obtained should the therapy prove highly effective and obviate the need for heart transplants.
- A reviewer expressed disappointment that the bulk of the preclinical efficacy data relies on echocardiography and noted other more reliable/robust imaging methods in place at the applicant institution.
PI and Planning Leader
- Reviewers praised the PI’s extensive clinical cardiothoracic surgery experience, expertise developing immunosuppressive protocols and participation in clinical stem cell research.
- The planning leader is an innovative and renowned physician scientist with experience developing a cardiac therapeutic.
- The excellence of entire assembled team contributed to the program’s likelihood of success.