Human iPSC-based personalized cell therapy of PD

 描述(申请人提供)：帕金森病(PD)是一种由中脑多巴胺(MDA)神经元进行性和选择性变性引起的运动综合征。帕金森病是最常见的运动障碍，在65岁以上的人口中有1%-2%受到影响。随着我们人口的老龄化，预计我们的医疗保健负担 系统将升级。目前，还没有任何治疗方法可以阻止或减缓帕金森氏症的进展。由于一种特定的细胞类型(即黑质中的A9-MDA神经元)的丢失是运动性帕金森病的主要原因，因此它是基于细胞治疗的最有前途的靶向疾病之一。事实上，大量的临床和临床前研究证明，一旦建立起无限、功能和安全的细胞源，细胞移植是治疗帕金森病的一种可行的治疗方案。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(IPSCs)是最有前途的细胞来源，可能导致个性化的细胞治疗，而不会出现免疫排斥和伦理学问题，如胚胎破坏。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的重新编程策略，有效地产生了高质量的IPSCs，鉴定和纯化了真正的MDA前体细胞，化学方法消除了剩余的未分化细胞，以及新的和有效的分化方法。基于这些有希望的数据，我们建议从散发性PD成纤维细胞中进一步建立临床级IPSCs，包括其特性、体外分化和丙二醛前体细胞的纯化。此外，我们将使用PD的啮齿动物和灵长类动物模型，分析和比较来源于人ESCs和IPSCs的MDA前体细胞在体内的功能结果。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调查。我们的建议将通过比较hESC和hPSC来源的丙二醛细胞在体外和体内的功能效率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垫脚石，最终导致新一代细胞替代疗法治疗帕金森病。

 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.