Parkinsons disease scalable iPSC autologous cell therapy

摘要： NINDS Create Bio Development Track U01工作将完成使IND能够进展细胞的研究 使用诱导多能干细胞(IPSC)衍生的多巴胺(DA)进行临床替代的范例 以及首次用于帕金森氏病(PD)自体移植的临床试验。细胞 中脑多巴胺(MDA)神经元的替代疗法提供了细胞和突触修复 帕金森病患者的大脑，并解决帕金森氏症的运动症状以及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，移植的丙二醛神经元保持健康 并能在数十年内提供显著的治疗效果。虽然胎儿细胞移植不能扩展到 IPSCs患者人数较多，需要免疫抑制，是一种很有前途的替代细胞来源。IPSCs 从帕金森病患者身上产生的细胞可以分化为中脑多巴胺能细胞，冷冻后用于 自体移植。 U01计划在5年内包括四个具体目标中的里程碑，其中包括I期临床 在人类帕金森病患者身上进行试验。在具体目标1中，我们将把剩余的丙二醛神经元产品质量 控制cGMP设施中的合格化验，执行FDA指导的辅料质量控制 临床产品，并产生丙二醛神经元，用于IND使能研究。在具体目标2中，最终目标-- 将进行使能研究，以测试人类的安全性(致瘤性和生物分布)和疗效 IPSC衍生的啮齿动物冷冻解冻的丙二醛神经元，以及计划中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将包括为调查员发起的IND包的准备和提交 第一阶段临床试验、帕金森病患者招募和自体cGMP ipSCs和MDA的产生 以及对冷冻保存的临床产品进行释放标准测试。最后，具体目标4是第一个- 在6名散发性帕金森病患者中进行的I期人体临床干预开放临床试验，以测试其安全性 冷冻解冻的丙二醛神经元自体移植的效果。 这项高度创新的自体CMC iPS细胞技术U01建议用于PD的细胞替代临床试验 Patients为成功开展PD和PD的细胞治疗提供了必要的步骤和探索 几种神经性疾病。

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.