Human iPSC-based personalized cell therapy of PD

基于人类 iPSC 的 PD 个性化细胞治疗

基本信息

批准号：
9127537
负责人：
Kwang-Soo Kim
金额：
$ 66.07万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127537
关键词：
Address Affect Agonist Behavioral Biological Cell Line Cell Survival Cell Therapy Cell Transplantation Cell surface Cells Chemicals Clinical Clinical Research Corpus striatum structure Data Defect Development Disease Disease model Dopamine Elderly Embryo Ensure Epigenetic Process Ethical Issues Ethics Exhibits Fibroblasts Funding Gene Expression Generations Goals Healthcare Systems Human Immune In Vitro Lead Lesion MPTP Poisoning Metabolic Methods MicroRNAs Midbrain structure Modeling Molecular Monkeys Motor Movement Disorders Mus Parkinson Disease Patients Physiological Population Primates Property Regimen Replacement Therapy Rodent Rodent Model Safety Secondary to Source Staging Stem Cell Research Stem cells Substantia nigra structure Syndrome Testing Therapeutic Tissues Transgenes Transplantation Undifferentiated Viral aging population base behavioral outcome cell type clinical application dopaminergic neuron epigenetic memory fetal functional outcomes human disease human embryonic stem cell improved in vivo induced pluripotent stem cell insight neurotransmission novel open label optogenetics preclinical study progenitor public health relevance relating to nervous system research study standard care stem cell technology synucleinopathy tumor

项目摘要

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.

描述（由适用提供）：帕金森氏病（PD）是一种突触核酸，其运动综合征是由中脑多巴胺（MDA）神经元进行性和选择性变性引起的。 PD是最常见的运动障碍，影响了65岁以上人口的1-2％。随着人口老龄化，预计会燃烧我们的医疗保健系统将升级。目前，没有可以停止或减慢帕金森氏病进展的治疗方法。由于特定细胞类型的丧失（即，底虫中的A9 MDA神经元）是运动PD的主要原因，因此它是基于细胞治疗的最具验证靶标疾病之一。实际上，许多临床和临床前研究表明，一旦可以建立有限，功能性和安全的细胞来源，细胞移植是一种可行的PD治疗治疗方案的原则证明。在各种潜在的细胞源中，我们推测患者衍生的诱导多能干细胞（IPSC）代表了最有前途的细胞来源，并且可能导致个性化的细胞疗法，而无需免疫排斥和伦理问题，例如胚胎破坏。为了支持这一点，在上一个融资周期中，我们取得了重大进展，例如建立基于机制的新型重编程策略，这些策略有效地产生了高质量的IPSC，对正宗MDA祖细胞的识别和净化，化学方法，消除剩余的不侵入性细胞，以及新颖的细胞，新颖和有效的分化方法。基于这些有希望的数据，我们建议从弹性PD成纤维细胞中进一步建立IPSC的临床级IPSC，包括它们的表征，其体外分化和MDA祖细胞的净化。此外，我们将使用PD的啮齿动物和私有模型来分析和比较从人ESC和IPSC衍生的MDA祖细胞的体内功能结果。这些移植研究的生物学和行为结果将长期进行系统研究。我们的建议将通过比较体外和体内的HESC和HIPSC衍生的MDA细胞的功能有效性来解决患者特异性细胞疗法的实际和主要问题，并将提供宝贵的见解和踏入岩石，最终导致PD的新产生的细胞替代疗法。