Parkinsons Disease Scalable iPSC Autologous Cell Therapy

摘要： 这是一个修订后的应用程序，经过修改以完全响应审查者的评论和FDA的互动，因为 申请(FDA Pre-IND会议于9月9日举行25,2018年)。拟议的工作将完成IND使能 使用诱导多能干细胞(IPSC)将细胞替代范例应用于临床的研究进展- 派生的多巴胺(DA)神经元，以及帕金森病自体移植的首例临床试验 疾病(PD)。中脑多巴胺(MDA)神经元的细胞替代疗法提供细胞和突触 帕金森病患者大脑的修复，并解决帕金森病的运动症状和左旋多巴诱导的 运动障碍。我们之前的胎儿细胞移植工作表明，在帕金森病患者中移植了丙二醛神经元 保持健康，并可在数十年内提供显著的治疗效果。而胎儿细胞移植 不能扩展到更大的患者群体，并且需要免疫抑制，iPSCs是一种很有前途的 另一种细胞来源。帕金森病患者产生的IPSCs可分化为中脑多巴胺能 冷冻的细胞，用于自体移植。 NINDS Create Bio Development Track U01建议书为期5年，包括4年内的里程碑 具体目标，包括在人类帕金森病患者中进行I期临床试验。在具体目标1中，我们将转移 其余的丙二醛神经元产品质量控制分析在cGMP设施中进行资格鉴定，执行FDA- 指导临床产品辅料的质量控制，生产用于工业生产的丙二醛神经元。 使研究成为可能。在具体目标2中，将进行决定性的启用IND的研究，以测试安全性 人IPSC来源的冻融丙二醛神经元在体外的致瘤性和生物分布 啮齿动物，以及在非人类灵长类动物中测试计划中的临床给药装置。具体目标3将 包括IND包准备和提交研究人员发起的第一阶段临床试验、招募 帕金森病患者自体cGMP、ipSCs和丙二醛神经元的产生及释放标准 对冷冻保存的临床产品进行检测。最后，特定目标4是人类第一个临床阶段I 对6例散发性帕金森病患者进行的介入性、开放标记临床试验，以测试其安全性和有效性。 冻融丙二醛神经元的自体移植。 这项高度创新的自体CMC iPS细胞技术U01建议在 帕金森病患者为成功开展帕金森病细胞疗法提供了必要的步骤和探索 以及几种神经性疾病。

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.