Bottlenecks of the clinical development of pluripotent stem cell based therapy

Human embryonic stem cells (hESCs) can self-renew for extended period of time in culture and retain the pluripotency to differentiate into all cell types in human body. Therefore, as a renewable source of therapeutically valuable cell types, hESCs hold great promise for human cell therapy. Consistent with this finding, significant progress has been achieved in establishing the conditions necessary to differentiate hESCs into several lineages of biologically active cells, including cardiomyocytes for treating heart diseases, oligodendroglial progenitors for spinal cord injury, pancreatic β cells for Type I diabetic patients, and neural stem cells for neurodegenerative diseases. These rapid progresses have led to two phase 1 clinical trials to treat spinal cord injury and macular degeneration. Despite these progresses, several major obstacles remain to be addressed prior to successful development of hESC-based regenerative medicine. For example, the differentiation and purification of hESC-derived cells need to be optimized to improve the efficacy and avoid teratomas associated with undifferentiated hESCs. Another major obstacle is the immune-mediated rejection of hESC-derived cells by the recipient because these cells express alloantigens that differ from those of the recipient patients. While allograft rejection can be delayed if the recipient's immune system is persistently suppressed, long-term chronic immunosuppression greatly increases the risk for cancer and infection, raising the issue of risk and benefit ratio of hESC-based therapy. We are developing novel strategies to resolve these bottlenecks in clinical development of hESC-based therapy.

Recent breakthrough of induced pluripotent stem cells (iPSCs), which can be reprogrammed from somatic cells of individual patient with defined factors and are similar to hESCs in the context of their unlimited self-renewal capability and pluripotency, could provide ideal cell source for transplantation into the same patients by avoiding graft rejection in the patient. In addition, the disease-specific iPSCs can be used as human disease models for more reliable testing of the efficacy and toxicity of drugs. However, our recent studies have indicated that the cells derived from mouse iPSCs might be immunogenic in the syngenic recipients. Others have shown that iPSCs might be genetically unstable. We are developing safe and efficient approach to generate iPSCs from human patients. In addition, we will study the immune response and tolerance of human iPSC-derived grafts during transplantation. Resolving these issues will greatly facilitate the development of iPSCs into stem cell therapy and disease models for drug discovery.