Human neural stem cell therapy for the treatment of cervical spinal cord injury (

描述（由申请人提供）：我们先前证明了人中枢神经系统干细胞（HuCNS-SC）在多种胸脊髓损伤（SCI）啮齿动物模型中的临床前疗效。在损伤后（dpi）9、30和60天移植的HuCNS-SC植入、存活、迁移，并表现出向少突胶质细胞和神经元的主要分化。重要的是，移植的细胞促进了运动功能的恢复，并且在这些移植时间中的每一个都没有显示出异常性疼痛的证据。这些数据促成了一项针对胸部SCI慢性损伤患者的I/II期SwissMedic试验;首例患者于2011年9月在苏黎世大学接受HuCNS-SC治疗。严重的是，52%的SCI临床病例发生在颈椎节段。以慢性SCI人群为目标，可产生更大的受试者队列，并有利于临床安全性和有效性评估（例如，自发恢复是一个严重的混淆因素）。治疗引起的SCI改善的鉴别部分取决于自发恢复率。自发恢复在急性胸部受试者中最高，在慢性颈部受试者中最低。据估计，一项急性胸部SCI试验需要多达225-250名ASIA A受试者和1，100名ASIA B受试者才能检测到中度效应。相比之下，慢性颈脊髓损伤试验可能需要少至25名ASIA A受试者和50名ASIA B受试者。此外，与胸部水平的类似增益相比，颈部区域的小功能增益提供了成比例的更大的生活质量变化。我们已经使用免疫缺陷Rag 2g/c小鼠产生单侧颈部SCI模型以优化异种移植，并且证明HuCNS-SC的9dpi移植促进运动功能的恢复而没有副作用，确立了HuCNS-SC的临床前功效。该团队已经在使用HuCNS-SC的临床翻译方面拥有相当丰富的经验，并以pre-preIND咨询的形式向FDA寻求了颈椎SCI适应症的初步反馈。该提案基于我们与FDA的互动，旨在扩展我们目前的颈椎SCI疗效数据，以评价预期临床细胞批次HuCNS-SC的疗效和长期安全性/毒理学，解决以下具体目标：目标1：在9 dpi移植单侧颈椎SCI小鼠模型中建立HuCNS-SC CCL的疗效和试验细胞递送部位。目的2：在60 dpi移植单侧颈部SCI小鼠模型中建立HuCNS-SC CCL的功效和测试细胞递送位点。目的3：评估HuCNS-SC CCL在自主神经反射异常啮齿动物模型中的安全性。目的4：在已建立的单侧颈椎SCI小鼠模型中确定HuCNS-SC CCL的长期安全性/毒理学。目标5：如果FDA在第2年的IND前会议上要求，确定HuCNS-SC的疗效和安全性/毒理学 CCL在第二个物种（ATN大鼠），使用混合研究设计和颈部SCI大鼠接受补充免疫抑制与抗sialoGM 1抗体治疗。本项目的目的是使该HuCNS-SC临床细胞批次用于颈脊髓损伤的IND申请成为可能 作为治疗目标。

DESCRIPTION (provided by applicant): We previously demonstrated pre-clinical efficacy of Human Central Nervous System Stem Cells (HuCNS-SC) in multiple rodent models of thoracic spinal cord injury (SCI). HuCNS-SC transplanted at 9, 30, and 60 days post-injury (dpi) engraft, survive, migrate, and exhibit predominant differentiation into oligodendrocytes and neurons. Critically, transplanted cells promoted recovery of locomotor function and showed no evidence of allodynia at each of these transplantation times. These data contributed to a Phase I/II SwissMedic trial targeting chronically injured individuals suffering from thoracic SCIs; the first patient received HuCNS-SC in September 2011 at the University of Zurich. Critically, 52% of clinical cases of SCIs occur at the cervical level. Targeting the chronic SCI population yields a much larger subject cohort and advantages for clinical safety and efficacy assessment (e.g. spontaneous recovery is a significant confound acutely). Discrimination of a therapy induced improvement for SCI is dependent, in part, on the spontaneous recovery rate. Spontaneous recovery is highest in acute thoracic subjects, and lowest in chronic cervical subjects. An acute thoracic SCI trial has been estimated to require as many as 225-250 ASIA A subjects and 1,100 ASIA B subjects to detect a moderate effect. In contrast, a chronic cervical SCI trial may require as few as 25 ASIA A subjects, and 50 ASIA B subjects. Further, a small gain of function in the cervical region affords a proportionally greater change in quality of life compared to a similar gain at the thoracic level. We have generated a unilateral cervical SCI model using immunodeficient Rag2g/c mice to optimize xeno-engraftment, and demonstrated that 9 dpi transplantation of HuCNS-SC promotes recovery of locomotor function with no adverse effects, establishing pre-clinical efficacy of HuCNS-SC. The UCI-StemCells Inc. team already has considerable experience in clinical translation using HuCNS-SC and has sought preliminary feedback from the FDA for a cervical SCI indication in the form of a pre-preIND consultation. This proposal is based on our FDA interactions and seeks to expand our current cervical SCI efficacy data to evaluate the intended clinical cell lot of HuCNS-SC for both efficacy and long-term safety/toxicology addressing the following Specific Aims: Aim 1: Establish efficacy and test cell delivery site for the HuCNS-SC CCL in a 9 dpi transplantation unilateral cervical SCI mouse model. Aim 2: Establish efficacy and test cell delivery site for the HuCNS-SC CCL in a 60 dpi transplantation unilateral cervical SCI mouse model. Aim 3: Assess the safety of the HuCNS-SC CCL in a rodent model of autonomic dysreflexia. Aim 4: Establish long-term safety/toxicology of the HuCNS-SC CCL in the established unilateral cervical SCI mouse model. Aim 5: If dictated by the FDA in a pre-IND meeting in Year 2, establish efficacy and safety/toxicology for the HuCNS-SC CCL in a second species (ATN rat), using a hybrid study design and cervical SCI rats receiving supplemental immunosuppression with anti-sialoGM1 antibody treatment. The aims of this project will enable IND application for the use of this HuCNS-SC clinical cell lot for cervical SCI as a therapeutic target.