Developing induced pluripotent stem cells into human therapeutics and disease models

Funding Type: 
Early Translational I
Grant Number: 
Award Value: 
Disease Focus: 
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all the cell types in the human body, and thus hold great promise for cell replacement therapy. However, one major problem for hESC-based therapy is that the cells derived from hESCs will be rejected by the recipient and can only be tolerated under persistent immunosuppression, which itself can cause cancer and infection. Recent development of induced pluripotent stem cells (iPSCs), which are generated from somatic cells of individual patient with defined factors and very similar to hESCs, could provide ideal cell source for transplantation 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, there are several major bottlenecks that prevent the development of iPSCs in human therapy and drug discovery. The overall goal of this proposal is to resolve the major bottlenecks remained in human iPSC biology to make it feasible for human therapy and drug discovery. We propose to develop safe and efficient approach to generate iPSCs from human patients. We propose to develop strategies to eliminate the risk of teratomas associated with the undifferentiated iPSCs. We propose to develop mouse model with functional human immune system to study the immune responses and tolerance during transplantation. Resolving these bottlenecks will greatly facilitate the development of hESCs into stem cell therapy and disease models for drug discovery.

Statement of Benefit to California: 

Diabetes and heart diseases remain the most costly diseases in our State and Nation. In the case of diabetes, 1 of every 10 Californians (2.7 million) were afflicted with diabetes in 2007, costing the State $24.5 billion annually. There is a significant increase in the occurrence of both types of diabetes in youths under 18 years of age (0.16% of youth <18 yr have type 1 diabetes nationally). Simply put, diabetes is having devastating consequences on both those afflicted and on State/National healthcare costs, and, given the staggering rise in both occurrence and costs, diabetes possesses the potential to completely overwhelm our healthcare system. There remains an urgent and critical need for a cell-based cure of diabetes. There is hope, since transplantation of functional β cells from human donors has been validated clinically to cure diabetes.

While significant progress has been made in the derivation of functional β cells and cardiomyocytes from human ES cells, these allogenic cells will be rejected by the recipient upon transplantation unless the immune system of the recipient is persistently suppressed. However, immune suppression itself has severe consequences with significantly increased risk of cancer and infection. This problem might be resolved by the recent breakthrough in induced pluripotent stem cell (iPSCs), which can be reprogrammed from somatic cells of human patients by defined factors and thus can provide a renewable source of autologous cells for transplantation. In addition, the disease-specific iPSCs will provide the much needed disease models to more reliably predict the drug responses in humans. With our significant progress in producing iPSCs without viral vectors or permanent genetic modification, our proposed research will resolve the major bottlenecks that hinder the development of iPSCs into human therapy and drug discovery. If successful, the funding spent now on research is nominal when compared to the billions that will be saved in treatment costs and the improved quality of life for patients.

Progress Report: 

Human induced pluripotent stem cells (hiPSCs), reprogrammed from somatic cells with defined factors, are similar to human ES cells (hESCs) and could provide ideal cell source for transplantation by avoiding immune rejection. In addition, disease-specific hiPSCs could provide improved disease models to predict drug responses in humans. The permanent genetic modification by random viral integration and spontaneous reactivation of reprogramming factors lead to cancer risk and abnormal differentiation. During the past year, we have made progresses to develop a combination of chemical and episomal approaches to reprogram human cells into iPSCs without genetic modifications. We have developed the constructs for the pre-transplant strategies to eliminate the teratomas risk of undifferentiated iPSCs. We have started to improve conditions for iPSC differentation into beta cells. In addition, we developed mouse models reconstituted with human immune system to enable us to study the immunogenicity and tolerance of cells derived from isogenic iPSCs.

During the past year, we have made significant progress in the proposed research. One most important finding is the discovery of the immunogenicity of the cells derived from induced pluripotent stem cells (iPSCs). This immunogenicity is due to the abnormal gene expression during the differentiation of iPSCs. This finding, published in the journal Nature, indicates that we need to perform more research on iPSCs before moving forward into clinical trial. Another major finding is the discovery of a safer way to improve the efficiency of iPSC production. In addition, we have made some progress in developing a genetic approach to eliminate the teratomas risk associated with the undifferentiated pluripotent stem cells.

During the past funding period, we have accomplished the established milestones. We have compared the genomic stability of iPSCs generated with various approaches. We have developed a genetic approach to eliminate the teratomas risk associated with undifferentiated pluripotent stem cells. We have evaluated the immunogenicity of cells derived from human iPSCs.

We have achieved the milestones and completed the proposed research during the no-cost extension period.