Parkinsons disease scalable iPSC autologous cell therapy

摘要： NINDS CREATE Bio Development Track U 01工作将完成IND使能研究，以进展细胞 使用诱导多能干细胞（iPSC）衍生的多巴胺（DA）替代范式进入临床 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 用中脑多巴胺（mDA）神经元的替代疗法提供了脑内的细胞和突触修复。 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，移植的mDA神经元保持健康 并且可以提供数十年的显著治疗益处。虽然胎儿细胞移植不能扩展到 由于iPSC具有更大的患者群体并且需要免疫抑制，因此iPSC是一种有前途的替代细胞来源。iPSCs 从PD患者产生的细胞可以分化成中脑多巴胺能细胞，冷冻并用于 自体移植 U 01提案在5年内由四个特定目标内的里程碑组成，其中包括I期临床 在PD患者中进行的试验。在具体目标1中，我们将把剩余的mDA神经元产品质量 在cGMP设施中进行确认的控制试验，对 临床产品，并产生用于IND使能研究的mDA神经元。在具体目标2中，明确的IND- 将进行可行性研究，以检测人用药物的安全性（致瘤性和生物分布）和疗效。 啮齿动物中iPSC衍生的冷冻解冻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将包括研究者发起的IND包装准备和备案 I期临床试验，招募PD患者并产生自体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。第4章是第一次-- 在6例散发性PD患者中进行的人体I期干预性、开放标签临床试验，以检测安全性 和冻融mDA神经元自体移植的功效。 这种高度创新的自体CMC iPS细胞技术U 01建议用于PD的细胞替代临床试验 为开发成功的PD细胞治疗提供了必要的步骤和探索， 几种神经系统疾病

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.