Human iPSC-Based Personalized Cell Therapy of PD

基于人类 iPSC 的个性化 PD 细胞疗法

基本信息

批准号：
10678012
负责人：
Kwang-Soo Kim
金额：
$ 70.51万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678012
关键词：
Address Affect Allogenic Alzheimer&apos s Disease Animal Model Autologous Autologous Transplantation Behavioral Brain Cell Differentiation process Cell Fate Control Cell Line Cell Therapy Cell Transplantation Cells Characteristics Chemicals Clinical Clinical Research Corpus striatum structure DNA Development Dopamine Embryo Ethics Fetus Genetic Goals Graft Survival Harvest Human Immune response Immunologic Tests Immunosuppression In Vitro Individual Lesion Medical Messenger RNA Metabolic Metabolic Control Metabolism Methods MicroRNAs Midbrain structure Molecular Motor Mus Neurodegenerative Disorders Neurons Nude Rats Outcome Oxidopamine Parkinson Disease Pathologic Pathway interactions Patients Pharmaceutical Preparations Physiological Population Production Property Protocols documentation Regimen Rodent Model SIRT1 gene Safety Societies Source Standardization Stem Cell Research Substantia nigra structure Synapses Technology Testing Therapeutic Time Tissues Tracer Transplantation Undifferentiated Variant Wheat Germ Agglutinins aging population behavior test cell replacement therapy cell type clinical implementation cost effective dopaminergic neuron epigenomics fetal first-in-human genome integrity human disease human embryonic stem cell human old age (65+)human pluripotent stem cell humanized mouse improved in vivo in vivo evaluation individual variation induced pluripotent stem cell induced pluripotent stem cell technology mRNA delivery motor disorder motor symptom mouse model neural neurosurgery novel open label pre-clinical progenitor promoter prototype reinnervation sporadic Parkinson&apos s Disease transcriptomics tumorigenic

Address Affect Allogenic Alzheimer&apos s Disease Animal Model Autologous Autologous Transplantation Behavioral Brain Cell Differentiation process Cell Fate Control Cell Line Cell Therapy Cell Transplantation Cells Characteristics Chemicals Clinical Clinical Research Corpus striatum structure DNA Development Dopamine Embryo Ethics Fetus Genetic Goals Graft Survival Harvest Human Immune response Immunologic Tests Immunosuppression In Vitro Individual Lesion Medical Messenger RNA Metabolic Metabolic Control Metabolism Methods MicroRNAs Midbrain structure Molecular Motor Mus Neurodegenerative Disorders Neurons Nude Rats Outcome Oxidopamine Parkinson Disease Pathologic Pathway interactions Patients Pharmaceutical Preparations Physiological Population Production Property Protocols documentation Regimen Rodent Model SIRT1 gene Safety Societies Source Standardization Stem Cell Research Substantia nigra structure Synapses Technology Testing Therapeutic Time Tissues Tracer Transplantation Undifferentiated Variant Wheat Germ Agglutinins aging population behavior test cell replacement therapy cell type clinical implementation cost effective dopaminergic neuron epigenomics fetal first-in-human genome integrity human disease human embryonic stem cell human old age (65+)human pluripotent stem cell humanized mouse improved in vivo in vivo evaluation individual variation induced pluripotent stem cell induced pluripotent stem cell technology mRNA delivery motor disorder motor symptom mouse model neural neurosurgery novel open label pre-clinical progenitor promoter prototype reinnervation sporadic Parkinson&apos s Disease transcriptomics tumorigenic

展开

项目摘要

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.

抽象的帕金森氏病（PD）是仅次于阿尔茨海默氏病的第二常见神经退行性疾病，影响65岁以上人口的1-2％。随着我们的老龄化，预计会燃烧我们的社会将大大升级。目前，没有可以停止或扭转进展的治疗方法 PD。因为遗传中脑中脑多巴胺（MDA）神经元的丧失是Nigra，是 PD中运动功能障碍的主要原因，它是基于细胞治疗的承诺靶标。确实，许多研究已经证明了细胞移植是PD的可行治疗方案的原理证明可以从不同的个体中建立无限，功能和安全的细胞来源背景。在各种潜在的细胞来源中，患者衍生的人诱导多能干细胞（HIPSC）代表一个有望的细胞来源，可以允许个性化的细胞疗法，而无需道德或医学同种异细胞移植所需的免疫抑制等问题。达到这个长期目标，在过去的十年中，我们发现了一种新型的分子途径，而代谢重编程，明确鉴定出涉及的microRNA，开发了一种化学方法，以消除剩余的未分化具有肿瘤势的细胞，建立了新的重编程方法，以产生临床IPSC和体外分化方法以产生更健康的MDA细胞，并改善了增加的神经外科方法移植物存活率，导致零星PD患者的首次自体细胞疗法。同时，我们的进步揭示了几个基本和实际挑战，必须解决这些挑战，以充分实现基于HIPSC的自体细胞治疗PD的潜力，包括进一步发展更健壮，更安全基于分子机制的重新编程和体外分化方法在细胞脂肪调节过程中重新编程。我们建议解决这些基本和实际问题患者特定的细胞疗法并建立一个可以为PD患者提供个性化细胞疗法的平台不管它们的遗传背景如何。