Human iPSC-based personalized cell therapy of PD

 描述（由申请人提供）：帕金森病（PD）是一种突触核蛋白病，其运动综合征由中脑多巴胺（mDA）神经元的进行性和选择性变性引起。PD是最常见的运动障碍，影响65岁以上人群的1-2%。随着人口老龄化，预计我们的医疗保健负担 系统将升级。目前，没有治疗方法可以阻止或减缓帕金森病的进展。因为特定细胞类型（即，黑质A9 mDA神经元是运动性PD的主要病因，是细胞治疗最有希望的靶点之一。事实上，许多临床和临床前研究证明，一旦可以建立无限的，功能性的和安全的细胞来源，细胞移植是PD治疗的可行治疗方案。在各种潜在的细胞来源中，我们推测患者来源的诱导多能干细胞（iPSC）是最有前途的细胞来源，可能会导致个性化的细胞治疗，而不会产生免疫排斥反应和胚胎破坏等伦理问题。为了支持这一点，在上一个资助周期中，我们取得了重大进展，例如建立了基于机制的新型重编程策略，有效地产生高质量的iPSC，鉴定和纯化真正的mDA祖细胞，消除剩余未分化细胞的化学方法，以及新型有效的分化方法。基于这些有希望的数据，我们提出进一步建立从散发性PD成纤维细胞产生临床级iPSC，包括它们的表征、它们的体外分化和mDA祖细胞的纯化。此外，我们将使用啮齿动物和灵长类动物PD模型分析和比较来自人ESC和iPSC的mDA祖细胞的体内功能结果。这些移植研究的生物学和行为学结果将在长期范围内进行系统研究。我们的提案将通过比较hESC和hiPSC衍生的mDA细胞在体外和体内的功能功效来解决患者特异性细胞治疗的实际和主要问题，并将提供宝贵的见解和踏脚石，最终导致新一代PD细胞替代疗法。

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a synucleinopathy whose motor syndrome is caused by progressive and selective degeneration of midbrain dopamine (mDA) neurons. PD is the most frequent movement disorder, affecting 1-2% of the population over the age of 65. With our aging population, it is anticipated that the burden on our health care system will escalate. Currently, there are no treatments that can halt or slow down the progression of Parkinson's disease. Because the loss of a specific cell type (i.e., A9 mDA neurons in the substantia nigra) is the main cause of motor PD, it is one of most promising target diseases for cell-based therapy. Indeed, numerous clinical and preclinical studies demonstrated the proof-of-principle that cell transplantation is a viable therapeutic regimen for PD treatment once a limitless, functional, and safe cell source can be established. Among various potential cell sources, we speculate that patient-derived induced pluripotent stem cells (iPSCs) represent the most promising cell source and may lead to personalized cell therapy without immune rejection and ethical issues such as embryo destruction. In support of this, during the last funding cycle, we have made significant progress such as the establishment of mechanism-based novel reprogramming strategies that efficiently generate high quality iPSCs, identification and purification of authentic mDA progenitors, chemical methods to eliminate remaining undifferentiated cells, and novel and efficient differentiation methods. Based on these promising data, we propose to further establish generation of clinical grade iPSCs from sporadic PD fibroblasts, including their characterization, their in vitro differentiation, and the purificaton of mDA progenitors. Furthermore, we will analyze and compare in vivo functional outcomes of mDA progenitors derived from human ESCs and iPSCs using both rodent and primate models of PD. Biological and behavioral outcomes of these transplantation studies will be systematically investigated in a long-term scale. Our proposal will address practical and major issues of patient-specific cell therapy by comparing the functional efficacies of hESC- and hiPSC-derived mDA cells both in vitro and in vivo and will provide invaluable insights and stepping-stones, eventually leading to a new generation of cell replacement therapy for PD.