Parkinsons Disease Scalable iPSC Autologous Cell Therapy

帕金森病可扩展 iPSC 自体细胞疗法

• 批准号: 10544119
• 负责人: OLIVER COOPER
• 金额: $ 196.13万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544119
• 关键词: Address; Affect; Agreement; Allogenic; Autologous; Autologous Transplantation; Biodistribution; Biological Assay; Blood; Boston; Bradykinesia; Brain; Cell Line; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Core Facility; Corpus striatum structure; Cryopreservation; Cyclic GMP; Dana-Farber Cancer Institute; Deep Brain Stimulation; Development; Devices; Diagnosis; Disease; Disease model; Dopamine; Dopaminergic Cell; Enrollment; Excipients; Family; Freezing; Future; Generations; Guidelines; Hospitals; Human; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunosuppression; Induced pluripotent stem cell derived neurons; Intervention; L-DOPA induced dyskinesia; Medical; Medical Care Costs; Midbrain structure; Motor; National Institute of Neurological Disorders and Stroke; Neurologic; Parkinson Disease; Parkinsonian Disorders; Patient Recruitments; Patients; Phase; Phase I Clinical Trials; Preparation; Procedures; Process; Published Comment; Qualifying; Quality Control; Rattus; Reagent; Research Personnel; Rodent; Safety; Somatic Cell; Source; Symptoms; Synapses; Technology; Testing; Therapeutic; Therapy Clinical Trials; Time; Transplant Recipients; Transplantation; Tremor; Tumorigenicity; Woman; Work; cell preparation; cell replacement therapy; clinical practice; dopaminergic neuron; experimental study; fetal; fetus cell; first-in-human; functional restoration; induced pluripotent stem cell; innovation; motor function improvement; motor symptom; nerve supply; nervous system disorder; nonhuman primate; open label; patient population; posture instability; pre-Investigational New Drug meeting; programs; putamen; repaired; safety and feasibility; safety testing; side effect; sporadic Parkinson' s Disease

Abstract: This is a revised application, modified to fully respond to reviewers’ comments and FDA interactions since the application (FDA pre-IND meeting held on Sept. 25, 2018). The proposed work will complete IND-enabling studies to progress cell replacement paradigms into the clinic using induced pluripotent stem cell (iPSC)- derived dopamine (DA) neurons, and a first-in-man clinical trial for autologous transplantation in Parkinson’s disease (PD). Cell replacement therapy with midbrain dopamine (mDA) neurons provides cellular and synaptic repair in the parkinsonian brain, and addresses both the motor symptoms of PD as well as levodopa-induced dyskinesias. Our previous fetal cell transplantation work shows that in PD patients transplanted mDA neurons remain healthy and can provide remarkable therapeutic benefit for decades. While fetal cell transplantations are not scalable for a larger patient population and require immunosuppression, iPSCs are a promising alternative cell source. iPSCs generated from PD patients can be differentiated into midbrain dopaminergic cells, frozen and used for autologous transplantation. The NINDS CREATE Bio Development Track U01 proposal over 5 years consists of milestones within four Specific Aims, that includes a Phase I clinical trial in human patients with PD. In Specific Aim 1 we will transfer the remaining mDA neuron product quality control assays for qualification in the cGMP facility, perform FDA- guided quality control of excipients for the clinical product, and produce mDA neurons to be used in IND- enabling studies. In Specific Aim 2, definitive IND-enabling studies will be performed to test the safety (tumorigenicity and biodistribution) and efficacy of human iPSC-derived frozen-thawed mDA neurons in rodents, as well as testing of the planned clinical delivery device in non-human primates. Specific Aim 3 will include IND package preparation and filing for an Investigator-initiated Phase I clinical trial, recruitment of patients with PD and generation of autologous cGMP iPSCs and mDA neurons as well as release criteria testing of the cryopreserved clinical product. Finally, Specific Aim 4 is a first-in-human clinical Phase I interventional, open-label clinical trial in 6 patients with sporadic PD, to test the safety and efficacy of autologous transplantation of frozen-thawed mDA neurons. This highly innovative autologous CMC iPS cell technology U01 proposal for cell replacement clinical trials in PD patients provides a necessary step and exploration for the development of successful cell therapy for PD and several neurological disorders.

摘要： 这是一份修订后的申请，修改后的申请完全回应了审评员的意见和FDA的互动， 申请（FDA于9月10日举行的IND前会议）25，2018）。拟议的工作将完成IND的启用 研究使用诱导多能干细胞（iPSC）将细胞替代范例进展到临床- 衍生的多巴胺（DA）神经元，以及帕金森氏症自体移植的首次人体临床试验 疾病（PD）。使用中脑多巴胺（mDA）神经元的细胞替代疗法提供细胞和突触功能。 修复帕金森病的大脑，并解决了运动症状的PD以及左旋多巴诱导的 运动障碍我们以前的胚胎细胞移植工作表明，在PD患者中移植mDA神经元， 保持健康，并可提供数十年的显著治疗益处。当胚胎细胞移植 对于更大的患者群体来说是不可扩展的，并且需要免疫抑制，iPSC是一种有前途的 替代细胞来源。从PD患者产生的iPSC可以分化为中脑多巴胺能神经元。 细胞，冷冻并用于自体移植。 NINDS CREATE Bio Development Track U 01提案在5年内包括四个里程碑 特定目的，包括在PD人类患者中进行的I期临床试验。在具体目标1中，我们将转移 在cGMP设施中进行认证的剩余mDA神经元产品质量控制测定，执行FDA- 指导临床产品辅料的质量控制，并生产用于IND的mDA神经元- 赋能研究。在特定目标2中，将进行确定性IND使能研究，以检测安全性 人iPSC衍生的冷冻-解冻的mDA神经元在小鼠中的生长（致瘤性和生物分布）和功效 啮齿类动物，以及在非人灵长类动物中测试计划的临床输送装置。第3章将 包括研究者发起I期临床试验的IND包装准备和备案， PD患者和自体cGMP iPSC和mDA神经元的产生以及释放标准 冷冻保存临床产品的检测。最后，Specific Aim 4是第一个人体临床I期 在6例散发性PD患者中进行的干预性、开放标签临床试验，旨在检测 冷冻-解冻的mDA神经元的自体移植。 这种高度创新的自体CMC iPS细胞技术U 01建议用于细胞替代临床试验， 帕金森病患者为发展成功的帕金森病细胞治疗提供了必要的步骤和探索 还有几种神经系统疾病