Human iPSC-Based Personalized Cell Therapy of PD

摘要 帕金森病（PD）是继阿尔茨海默病之后的第二种最常见的神经退行性疾病， 影响65岁以上人口的1-2%。随着人口老龄化，预计 我们的社会将大大升级。目前，没有治疗方法可以阻止或逆转进展 的PD。由于一种特定细胞类型的丢失，即黑质中的中脑多巴胺（mDA）神经元， 它是PD运动功能障碍的主要原因，是基于细胞的治疗的有希望的靶点。事实上，许多研究 已经证明了细胞移植是一种可行的PD治疗方案， 可以从具有不同遗传学特性的不同个体建立无限的、功能性的和安全的细胞来源。 背景在各种潜在的细胞来源中，患者来源的人诱导多能干细胞 hiPSC（hiPSC）代表了一种有前途的细胞来源，并且可以允许个性化的细胞疗法，而无需伦理或医学上的限制。 例如同种异体细胞移植所需的免疫抑制等问题。为了实现这一长期目标， 在过去的十年中，我们已经发现了一种新的代谢重编程的分子途径， 确定了具体涉及的microRNA，开发了一种化学方法，以消除剩余的未分化的 具有致瘤潜力的细胞，建立了新的重编程方法以产生临床级iPSC， 体外分化方法以产生更健康的mDA细胞，以及改进的神经外科方法以增加 移植物存活率，导致第一个自体细胞治疗散发性PD患者。同时我们的 取得的进展表明，要充分实现千年发展目标， 基于hiPSC的自体细胞治疗PD的潜力，包括进一步开发更稳健和更安全的 基于代谢基础分子机制的重编程和体外分化方法 在细胞命运调节过程中进行重编程。我们建议解决这些基本和实际问题， 患者特异性细胞治疗，并建立一个平台，使个性化的细胞治疗PD患者 不管他们的基因背景如何。

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.