Parkinsons disease scalable iPSC autologous cell therapy

帕金森病可扩展 iPSC 自体细胞疗法

• 批准号: 10543901
• 负责人: PENELOPE Jane HALLETT
• 金额: $ 16.4万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543901
• 关键词: Address; Autologous; Autologous Transplantation; Biodistribution; Biological Assay; Brain; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Clinical Trials; Cryopreservation; Cyclic GMP; Development; Devices; Disease; Dopaminergic Cell; Excipients; Freezing; Generations; Human; Immunosuppression; Intervention; L-DOPA induced dyskinesia; Midbrain structure; National Institute of Neurological Disorders and Stroke; Parkinson Disease; Parkinsonian Disorders; Patient Recruitments; Patients; Phase; Phase I Clinical Trials; Preparation; Process; Quality Control; Research Personnel; Rodent; Source; Synapses; Technology; Testing; Therapeutic; Therapy Clinical Trials; Transplant Recipients; Tumorigenicity; Work; cell replacement therapy; dopaminergic neuron; fetus cell; first-in-human; functional restoration; induced pluripotent stem cell; innovation; motor symptom; nervous system disorder; nonhuman primate; open label; patient population; programs; repaired; safety and feasibility; safety testing

Abstract: The NINDS CREATE Bio Development Track U01 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 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.

抽象的： NINDS CREATE Bio Development Track U01 工作将完成 IND 支持研究，以推进细胞进展 使用诱导多能干细胞 (iPSC) 衍生的多巴胺 (DA) 将替代范例引入临床 神经元，以及帕金森病（PD）自体移植的首次人体临床试验。细胞 使用中脑多巴胺 (mDA) 神经元的替代疗法可提供细胞和突触修复 帕金森病大脑，并解决帕金森病的运动症状以及左旋多巴引起的运动障碍。 我们之前的胎儿细胞移植工作表明，在PD患者中移植的mDA神经元仍然保持健康 并可以提供长达数十年的显着治疗效果。虽然胎儿细胞移植无法规模化 由于患者群体较多且需要免疫抑制，iPSC 是一种有前途的替代细胞来源。诱导多能干细胞 PD患者产生的细胞可以分化为中脑多巴胺能细胞，冷冻并用于 自体移植。 U01 提案历时 5 年，由四个具体目标中的里程碑组成，其中包括 I 期临床 在人类 PD 患者中进行的试验。在具体目标 1 中，我们将转移剩余的 mDA 神经元产品质量 在 cGMP 设施中进行资格控制测定，执行 FDA 指导下的辅料质量控制 临床产品，并生产用于 IND 研究的 mDA 神经元。在具体目标 2 中，明确的 IND- 将进行有利的研究来测试人类的安全性（致瘤性和生物分布）和功效 啮齿动物中 iPSC 衍生的冻融 mDA 神经元，以及计划的临床输送装置的测试 在非人类灵长类动物中。具体目标 3 将包括 IND 包准备和研究者发起的归档 I期临床试验，招募PD患者并生成自体cGMP iPSC和mDA 神经元以及冷冻保存的临床产品的释放标准测试。最后，具体目标 4 是第一个—— 在 6 名散发性 PD 患者中进行人体临床 I 期介入、开放标签临床试验，以测试安全性 冻融 mDA 神经元自体移植的效果和效果。 这项高度创新的自体 CMC iPS 细胞技术 U01 建议用于 PD 细胞替代临床试验 为PD和PD细胞疗法的成功开发提供了必要的步骤和探索 几种神经系统疾病。