Stem Cell-Derived Developmental Human Cortical Interneurons to Treat Intractable Epilepsy

干细胞衍生的发育性人类皮质中间神经元治疗难治性癫痫

基本信息

批准号：
10355921
负责人：
SANGMI CHUNG
金额：
$ 56.58万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355921
关键词：
Address Adult Affect Animal Model Antiepileptic Agents Behavioral Brain Cell Proliferation Cell Survival Cell Therapy Clinical Derivation procedure Development Devices Disinhibition Dose Electroencephalography Ensure Environment Epilepsy Ethical Issues Exhibits Frequencies GABA Agonists Ganglia Generations Glutamates Goals Graft Survival Growth Hippocampus (Brain)Histologic Homeostasis Human Image Analysis Interneuron function Interneurons Intervention Intractable Epilepsy Investigational Therapies Kainic Acid Laboratories Maintenance Measures Medial Methods Modeling Monitor Mus Nervous system structure Neurons Patients Pharmaceutical Preparations Pilot Projects Pluripotent Stem Cells Population Positioning Attribute Rabies Recurrence Refractory Reporting Research Risk Safety Seizures Side Specificity Synapses System Temporal Lobe Epilepsy Testing Therapeutic Three-Dimensional Image Time Translating Translations Transplantation Work brain circuitry clinical application clinical translation comorbidity density effective therapy efficacy evaluation excitatory neuron fetal hippocampal sclerosis human model human pluripotent stem cell in vivo imaging system induced pluripotent stem cell longitudinal analysis migratory population nerve supply nervous system disorder novel novel therapeutics postsynaptic preclinical study side effect stem cells tumor

项目摘要

Abstract Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with epilepsy suffer from intractable seizures that do not respond to antiepileptic drugs (AEDs). Neurosurgical interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cells (hPSCs)- derived medial ganglionic eminence (MGE)-type human developmental cortical interneurons (cINs) into epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the suppression of seizures and comorbid behavioral abnormalities. Furthermore, we have also determined the optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory populations of cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality. However, there are still important issues to address prior to the clinical translation of this promising restorative therapy; 1) what is the synaptic connection specificity of human developmental cINs in adult epileptic circuitry? 2) what are safe and optimal densities of human cIN grafts for inhibition of epileptic host circuitry? 3) do human developmental cIN grafts maintain long-term efficacy and safety in epileptic brains? To tackle these issues, we will test our hypothesis that human iPSC-derived developmental cINs with optimal grafting densities preferentially innervate host excitatory neurons and ameliorate seizure activity with long-term efficacy and safety. We will transplant migratory human cINs into Nod Scid gamma (NSG) mice with intrahippocampal kainic acid-induced temporal lobe epilepsy (KA-TLE), a model of human hippocampal sclerosis, the most common cause of drug-resistant epilepsy, and analyze grafted cINs’ synaptic integration specificity and host inhibition in the epileptic brains. The long-term maintenance of anti-epileptic efficacy will be extensively analyzed by 24/7 video-EEG recordings 3 months, 6 months and 9 months after transplantation. We will analyze the grafts immunohistochemically to determine the extent of cell survival, maturation, integration, and most importantly, cell proliferation as a measure of graft safety without risk of uncontrolled growth. Completion of these studies is pivotal for translating this experimental therapy into a viable therapeutic strategy for intractable epilepsy.

抽象的癫痫是一种严重的神经系统疾病，影响全球超过 6500 万人，其特点是不可预测的异常放电导致约三分之一的患者反复癫痫发作。癫痫患者患有顽固性癫痫发作，抗癫痫药物 (AED) 没有反应。干预措施和神经刺激装置仅对一小部分药物难治性患者有用癫痫发作，强调了开发新疗法的迫切需要，其中一项具有巨大前景的策略是：植入新的神经元以活性依赖性方式提供增强的 GABA 抑制。因此，利用胎儿神经元进行细胞治疗涉及实际和伦理问题。障碍，在我们之前的研究中，我们开创了人类多能干细胞（hPSC）的移植—— 衍生的内侧神经节隆起（MGE）型人类发育皮质中间神经元（cIN）癫痫小鼠大脑并证明它们整合到功能失调的电路中，并伴随着此外，我们还确定了癫痫发作和共病行为异常的抑制。人类 cIN 分化的最佳阶段，以确保最大程度地集成到宿主电路中以及安全性无肿瘤形成风险，并开发了一种有效生成这些安全且高度迁移的方法大量来自 hPSC 的 cIN 群体，使癫痫细胞疗法更接近现实。然而，在这种有希望的恢复剂临床转化之前，仍然有一些重要的问题需要解决。治疗；1) 成人癫痫回路中人类发育 cIN 的突触连接特异性是什么？ 2) 抑制癫痫宿主回路的人类 cIN 移植物的安全和最佳密度是多少？ 3) 人类 cIN 移植物的安全和最佳密度是多少？发育性 cIN 移植物能否在癫痫大脑中保持长期疗效和安全性？将检验我们的假设，即具有最佳移植密度的人类 iPSC 衍生的发育 cIN 优先神经支配宿主兴奋性神经元并改善癫痫活动，具有长期功效我们将迁移性人类 cIN 移植到海马内的 Nod Scid gamma (NSG) 小鼠中。红藻氨酸诱导的颞叶癫痫（KA-TLE），人类海马硬化模型，耐药性癫痫的常见原因，并分析移植cINs的突触整合特异性和宿主长期维持抗癫痫功效将主要是抑制癫痫大脑。我们将在移植后 3 个月、6 个月和 9 个月通过 24/7 视频脑电图记录进行分析。对移植物进行免疫组织化学分析，以确定细胞存活、成熟、整合的程度，以及最重要的是，细胞增殖作为移植物安全性的衡量标准，没有不受控制的生长风险。这些研究对于将这种实验疗法转化为可行的治疗策略至关重要顽固性癫痫。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From cells to insights: the power of human pluripotent stem cell-derived cortical interneurons in psychiatric disorder modeling.

从细胞到见解：人类多能干细胞衍生的皮质中间神经元在精神疾病模型中的力量。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Ni, Peiyan;Fan, Lingyi;Jiang, Youhui;Zhou, Chuqing;Chung, Sangmi
通讯作者：
Chung, Sangmi

Generation of neural organoids for spinal-cord regeneration via the direct reprogramming of human astrocytes.

通过人类星形胶质细胞的直接重编程生成用于脊髓再生的神经类器官。

DOI：
发表时间：
2023-03
期刊：
影响因子：
28.1
作者：
Xu, Jinhong;Fang, Shi;Deng, Suixin;Li, Huijuan;Lin, Xiaoning;Huang, Yongheng;Chung, Sangmi;Shu, Yousheng;Shao, Zhicheng
通讯作者：
Shao, Zhicheng

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

YBX1 介导的 PBMC 中 DNA 甲基化依赖性 SHANK3 表达和精神分裂症中皮质中间神经元的发育。

DOI：
发表时间：
2023-07
期刊：
影响因子：
0
作者：
Ni, Peiyan;Zhou, Chuqing;Liang, Sugai;Jiang, Youhui;Liu, Dongxin;Shao, Zhicheng;Noh, Haneul;Zhao, Liansheng;Tian, Yang;Zhang, Chengcheng;Wei, Jinxue;Li, Xiaojing;Yu, Hua;Ni, Rongjun;Yu, Xueli;Qi, Xueyu;Zhang, Yamin;Ma, Xiaohong;Deng, Wei
通讯作者：
Deng, Wei

Generation of Homogeneous Populations of Cortical Interneurons from Human Pluripotent Stem Cells.

从人类多能干细胞中产生同质的皮质中间神经元群。