Early Translational III
Heart failure is a major and ever-growing health problem affecting an estimated 5.8 million Americans with about half a million new cases every year. There are limited therapeutic options for heart failure. Heart transplantation is effective but has limited impact due to scarcity of donor organs and eventual immune rejection even under chronic immune suppression. Therefore, there is a clear unmet medical need to develop new effective therapies to treat heart failure. Human ES cell based cell therapy could provide a cure for heart diseases by providing renewable source of human cardiomyocytes (CMs) to restore lost cardiomyocytes and cardiac functions. In support of this notion, hESC-derived cardiomyocytes (hESC-CMs) can repopulate lost cardiac muscle and improve heart function in preclinical animal models of advanced heart failure. However, one key bottleneck hindering such clinic development is that hESC-CMs will be rejected by allogenic immune system of the recipients, and the typical immunosuppressant regimen is especially toxic for patients with heart diseases and leads to increased risk of cancer and infection. To resolve this bottleneck, I propose to develop a novel approach to protect the hESC-CMs from allogenic immune system. If successful, our approach will not only greatly improve the feasibility of developing hESC-CMs to treat heart failure but also has broad application in other hESC-based cell therapies for which allogenic immune rejection remains a major hurdle.
Statement of Benefit to California:
Heart disease is a leading cause of death and disability among Californians with an above average rate of mortality. It costs the State tremendous expenditure for the treatment and loss of productivity. There are limited therapeutic options for advanced heart diseases. In this context, heart transplantation is effective but limited by the shortage of donors. Therefore, there is clearly an urgent unmet medical need for new and effective therapies to treat heart failure. Human ES cell based cell therapy approach offers the unique potential to provide renewable source of cardiomyocytes to treat heart failure by restoring lost cardiomyocytes and cardiac function. However, one key bottleneck is that the allogenic hESC-derived cardiomyocytes will be immune rejected by recipients, and the typical immunosuppression regimen is especially toxic for fragile patients with heart diseases. In addition, chronic immune suppression greatly increases the risk of cancer and infection. Our proposed research is aimed to develop novel strategies to prevent allogenic immune rejection of hESC-derived cardiomyocytes without inducing systemic immune suppression. If successful, our approach will greatly facilitate the development of hESC-derived cardiomyocytes for treating heart disease and also has broad application in other hESC-based therapy for which allogenic immune rejection remains a bottleneck.
This Development Candidate Feasibility Award (DCF) application describes generation and testing of an approach to promote graft retention of allogeneic human embryonic stem cell derived cardiac myocytes (hESC-CM). The applicant has genetically modified an hESC line with two proteins to prevent their rejection by host T cells. First, the team will assess the ability of these modifications to protect hESC-CM from allogeneic rejection in an animal model with humanized immune system. They will then genetically modify a second hESC line that has been differentiated into cardiomyoctes and has shown benefit in preclinical heart failure models. hESC-CM will then be generated from these modified cells, and tested for both protection from allogeneic immune response and function in acute and chronic heart failure models. Objective and Milestones - The target product profile of the proposed development candidate contains the key attributes and is scientifically and clinically reasonable. - Milestones address key requirements to achieve the programs goals; however, quantifiable scientific and clinical success criteria are inadequate to assess milestone achievement. Rationale and Significance - Reviewers appreciate the magnitude of the roadblock that immune rejection presents to allogeneic stem cell therapies, as well as the risks associated with standard immunosuppression regimens in the target patient population. - Successful development of the proposed approach could yield a broad and significant impact upon cardiac disease that could potentially be extended to other allogeneic stem cell based regenerative therapies. - A weakness of the selected genetic modification lies in its ability to protect residual undifferentiated hESC from host immune surveillance, which therefore presents a potential cancer risk. Research Project Feasibility and Design - Reviewers were enthusiastic about the well-written proposal. - The team generated strong preliminary data that supports feasibility of the proposed approach. - Reviewers discussed the key strengths and weaknesses of the humanized mouse model, and strongly suggested the applicant incorporate complementary in vitro immunological monitoring assays into the experimental plan. - A panelist emphasized the importance of plans to assess potential systemic immunosuppression effects of the modified cells. Qualification of the PI and Research Team - The PI is highly qualified to lead this impressive multidisciplinary team, which encompasses all the expertise to successfully execute the proposed studies. - The PI and team have outstanding and relevant track records. - A communication plan was absent from the proposal. Collaborations Resources and Environment - Collaborations are critical to the success of the project. - Resources and environment at the host institution are outstanding for this translational effort, increasing its chances of success. Responsiveness to the RFA - The proposed project is responsive to the RFA’s goals.
- Shelly Heimfeld