Heart failure affects an estimated 5.8 million Americans with about half a million new cases every year. It is also one of the leading causes of death and loss of productivity in California. There is a clear unmet medical need to develop new therapies to treat patients with heart failure. Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body. Therefore, as a renewable source of various cell types in the body, hESCs hold great promise for the cell replacement therapy of many human diseases. In this context, significant progress has been made in the differentiation of hESCs into functional cardiomyocytes (CMs), providing the potential of cell replacement therapy to cure heart diseases through the restoration of lost cardiac function. However, one key bottleneck hindering the clinic development of hESC-derived CMs is that hESC-derived CMs will be rejected by allogenic immune system of the recipients, and the typical immunosuppressant regimen can be highly toxic for patients with heart diseases. To resolve this bottleneck and improve the feasibility of the hESC-based therapy of heart failure, we developed and validated a novel approach to protect the hESC-derived CMs from the allogenic human immune system in vivo.
Reporting Period:
Year 2
Heart failure is a major disease in California with limited therapeutic options. It costs the State tremendous expenditure in treatment and loss in productivity. While heart transplant is effective in treating the disease, this option is limited by the scarcity of heart donors and the modest graft survival rate (50%) ten years after transplantation. With their unlimited self-renewal capability and pluripotency to differentiate into all cell types in the body, human ES cells (hESCs) hold great promise for human cell therapy. Therefore, cell therapy approaches with hESC-derived CMs have the unique potential for a cure by restoring lost CMs and cardiac function. Despite significant progress in differentiating hESCs into CMs that are capable of partially restoring heart functions in myocardia infarction (MI) animal models, one key bottleneck remaining is that the allogenic hESC-derived CMs will be immune rejected by the recipients, and the typical immunosuppression regimen is especially toxic for patients with advanced heart diseases. By developing a novel approach to prevent allogenic immune rejection of hESC-derived CMs without the typical immunosuppression, we showed that genetically modified hESCs can be efficiently differentiated into cardiomyocytes, which exhibit characteristic electric physiological properties and are protected from allogenic immune rejection.
Reporting Period:
Year 3
Heart failure is a major disease in California with limited therapeutic options. It costs the State tremendous expenditure in treatment and loss in productivity. While heart transplant is effective in treating the disease, this option is limited by the scarcity of heart donors and the modest graft survival rate (50%) ten years after transplantation. With their unlimited self-renewal capability and pluripotency to differentiate into all cell types in the body, human ES cells (hESCs) hold great promise for human cell therapy. Therefore, cell therapy approaches with hESC-derived cardiomyocytes (CMs) have the unique potential for a cure by restoring lost CMs and cardiac function. Despite significant progress in differentiating hESCs into CMs that are capable of partially restoring heart functions in myocardial infarction (MI) animal models, one key bottleneck remaining is that the non recipient matched, or allogenic, hESC-derived CMs will be immune rejected by the recipients, and the typical immunosuppression regimen is especially toxic for patients with advanced heart diseases. Our research effort is to develop a novel approach to prevent allogenic immune rejection of hESC-derived CMs without the typical immunosuppression that induces systemic immune suppression.
We have developed hESC-CM that are resistant to allogeneic rejection and confirmed this property by performing allogeneic transplants using a humanized mouse model. This data suggests that our hESC-CM may act as universal donor heart cells for transplants into patients’ hearts. The ability of these cells to improve function of injured hearts will be tested in a preclinical model of myocardial infarction. This test will confirm the feasibility of our development candidate for further translation .”
Reporting Period:
NCE Progress Report
During NCE period, we have made progress in achieving the goal to test whether cardiomyocytes derived from CTLA4-Ig/PD-L1 expressing hESCs are functional in a rat myocardial infarction model. We sent personnels to Dr. Charles Murry lab at University of Washington to obtain the expertise in transplanting hESC-derived cardiomyocytes into MI rat model, and are preparing to complete the research within the next three months.
Grant Application Details
Application Title:
Human ES cell based therapy of heart failure without allogenic immune rejection
Public Abstract:
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.
