Human iPSC-Based Personalized Cell Therapy of PD

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1-2% of the population over the age of 65. With our aging population, it is anticipated that the burden on our society will significantly escalate. Currently, there are no treatments that can halt or reverse the progression of PD. Because the loss of a specific cell type, midbrain dopamine (mDA) neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is a promising target for cell-based therapy. Indeed, numerous studies have demonstrated the proof-of-principle that cell transplantation is a viable therapeutic regimen for PD once unlimited, functional, and safe cell sources can be established from different individuals with varying genetic backgrounds. Among various potential cell sources, patient-derived human induced pluripotent stem cells (hiPSCs) represent a promising cell source and may permit personalized cell therapy without ethical or medical issues such as immunosuppression required for allogeneic cell transplantation. Toward this long-term goal, during the last decade, we have uncovered a novel molecular pathway underlying metabolic reprogramming, identified specifically involved microRNAs, developed a chemical method to eliminate remaining undifferentiated cells with tumorigenic potential, established novel reprogramming methods to generate clinical grade iPSCs and in vitro differentiation methods to generate healthier mDA cells, and improved neurosurgical methods to increase the graft survival, leading to the first autologous cell therapy for a sporadic PD patient. At the same time, our progress revealed several fundamental and practical challenges that must be addressed to realize fully the potential of hiPSC-based autologous cell therapy for PD, including further development of more robust and safer reprogramming and in vitro differentiation methods based on molecular mechanisms underlying metabolic reprogramming during cell fate regulation. We propose to address these fundamental and practical issues of patient-specific cell therapy and to establish a platform that will enable personalized cell therapy for PD patients regardless of their genetic backgrounds.