IND-enabling studies for cell therapy in Parkinson's disease

帕金森病细胞疗法的 IND 研究

基本信息

批准号：
10760861
负责人：
Marcel Daadi
金额：
$ 46.52万
依托单位：
NEONEURON, LLC
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：
2023-09-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760861
关键词：
Address Adult Agreement Amphetamines Anatomy Animal Disease Models Animals Area Axon Biomedical Research Blood Cells Body Weight Bradykinesia Brain Cause of Death Cell Survival Cell Therapy Cell Transplantation Cells Chemistry Clinical Clinical Protocols Clinical Research Cognitive Cognitive deficits Control Groups Corpus striatum structure Development Devices Disease Disease Management Disease model Dopamine Dopaminergic Cell Dose Educational Intervention Engraftment Ethics Forelimb Good Manufacturing Process Graft Survival Immunocompromised Host Injections Intellectual Property Investigational Drugs Lesion Licensing Location MPTP Poisoning Medical Methodology Methods Midbrain structure Modeling Molecular Motor Neurodegenerative Disorders Neurosciences Oxidopamine Parkinson Disease Patients Persons Pharmaceutical Preparations Phase Pluripotent Stem Cells Preparation Procedures Production Proliferating Property Published Comment Rattus Recommendation Recovery of Function Regimen Research Institute Rotation Safety Skin Sleep disturbances Small Business Innovation Research Grant Small Business Technology Transfer Research Somatic Cell Source Step Tests Substantia nigra structure Symptoms Technology Testing Texas Therapeutic Time Tissues Toxicology Transplantation Tremor United States Food and Drug Administration Universities cell type clinical practice cognitive function cognitive training commercialization comparison control cost estimate design dopaminergic neuron fetal graft function image guided improved in vivo induced pluripotent stem cell insight manufacture motor function improvement nerve stem cell nerve supply nervous system disorder neurotransmission non-motor symptom nonhuman primate pars compacta preclinical study product development putamen response restoration safety assessment side effect stem stem cell technology stem cell therapy symptom treatment transcriptomic profiling transcriptomics transplantation therapy

项目摘要

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is currently incurable with significant unmet medical needs. In the US, over a million people suffer from this disease with an estimated cost of $27 billion per year. The mainstay of PD management is symptomatic treatment with drugs that increase dopamine in the striatum. However, the utility of these drugs is significantly curtailed by waning efficacy and debilitating side effects. Since PD stems from the degeneration of a single cell type, dopaminergic (DA) neurons that supply dopamine to a defined location the striatum, PD patients have been viewed as optimal candidate for cell transplantation therapy. Preclinical and clinical studies have demonstrated that transplantation of primary fetal midbrain DA neurons into the striatum, provide significant and sustained restoration of function. However ethical, practical and safety issues with using fetal aborted tissue and the recent progress in induced pluripotent stem cells (iPSCs), grafting trials in PD are beginning to re-emerge world-wide with a new focus on pluripotent stem cell technologies. However, clinical studies to date suggest that critical refinements in the cellular product, in the delivery method, and in the clinical protocol by considering the incorporation of adjunctive therapies, are essential to realize the potential of cell therapy in PD. NeoNeuron LLC has developed intellectual property on scalable and effective technologies for generating an unlimited supply of DA neurons from iPSCs and an image-guided methodology for delivering the cells into the target area of the brain enabling functional recovery in the rat and in the nonhuman primate models of PD. In preparation for our Investigational New Drug (IND) submission, NeoNeuron met with the U.S. Food and Drug Administration (FDA) and received recommendations to conduct optimal dose range for the cellular product, iPSC-DA neurons, in the immunocompromised rat model of PD. The company has established standard operating procedures to expand this product under current good manufacturing practice (cGMP), and to produce DA neurons that will be available as an off-the-shelf product. This feature is desirable for the development of the intended product for clinical use and for commercialization. In Aim 1 we will show evidence of dose-response and adequate levels of DA cell engraftment and survival for a 6-month duration in the hemi- parkinsonian rat model of PD. Aim 2 will assess the impact of adjunctive physical and cognitive training on motor and cognitive functions in the grafted animals. We will leverage single cell spatial transcriptomics profiling of the grafted cells to gain insights into the mechanisms of actions of our product and of the adjunctive training intervention in enhancing functional recovery. This Phase 1 will enable us to respond to the FDA recommendations by identifying the optimal dose level of iPSC-DA cell engraftment and durable effects in the PD model and to proceed with our planned Phase II SBIR proposal to establish the chemistry, manufacturing and controls, additional safety toxicology studies and device testing in nonhuman primates for the IND filing.

帕金森病（PD）是一种进行性神经退行性疾病，目前无法治愈，严重程度在美国，超过 100 万人患有这种疾病，估计费用为 27 美元。每年 10 亿美元，PD 治疗的主要手段是使用增加多巴胺的药物进行对症治疗。然而，这些药物的效用因疗效减弱和衰弱而显着减少。由于 PD 源于单细胞类型的退化，多巴胺能 (DA) 神经元将多巴胺供应到纹状体的特定位置，PD患者被视为细胞的最佳候选者移植治疗的临床前和临床研究表明，原代胎儿的移植治疗。中脑 DA 神经元进入纹状体，提供显着且持续的功能恢复。使用胎儿流产组织的伦理、实践和安全问题以及人工流产的最新进展多能干细胞 (iPSC)、PD 移植试验开始在世界范围内重新出现，新的重点是然而，迄今为止的临床研究表明，多能干细胞技术的关键改进。细胞产品、递送方法和临床方案中考虑纳入 NeoNeuron LLC 开发的辅助疗法对于实现 PD 细胞疗法的潜力至关重要。用于生成无限供应的 DA 神经元的可扩展且有效的技术的知识产权来自 iPSC 和图像引导方法，用于将细胞输送到大脑的目标区域，从而实现大鼠和非人灵长类 PD 模型的功能恢复为我们的研究做准备。新药（IND）提交，NeoNeuron与美国食品药品监督管理局（FDA）会面并获得建议对细胞产物 iPSC-DA 神经元进行最佳剂量范围公司建立了免疫功能低下的PD大鼠模型。根据现行良好生产规范 (cGMP) 扩展该产品，并生产 DA 神经元可作为现成产品使用，此功能对于目标产品的开发是理想的。在目标 1 中，我们将展示剂量反应和充分的证据。在偏侧帕金森病大鼠 PD 模型中 DA 细胞植入水平和 6 个月的存活率。目标 2 将评估辅助身体和认知训练对运动和认知功能的影响我们将利用移植细胞的单细胞空间转录组学分析来获得深入了解我们产品的作用机制以及增强辅助培训干预的作用机制第一阶段将使我们能够通过确定功能恢复来响应 FDA 的建议。 iPSC-DA 细胞植入的最佳剂量水平和 PD 模型中的持久效果，并继续我们的研究计划的第二阶段 SBIR 提案旨在建立化学、制造和控制以及额外的安全性用于 IND 申请的非人类灵长类动物的毒理学研究和设备测试。