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

描述(申请人提供)：我们先前证明了人类中枢神经系统干细胞(HuCNS-SC)在多种胸段脊髓损伤(SCI)啮齿动物模型中的临床前疗效。HuCNS-SC在损伤后9、30和60天移植，移植后存活、迁移，并显示出向少突胶质细胞和神经元的优势分化。关键的是，移植的细胞促进了运动功能的恢复，并且在每一次移植时都没有表现出痛觉异常的证据。这些数据促成了一项针对患有胸部SCI的慢性损伤患者的Swissmedic I/II期试验；第一名患者于2011年9月在苏黎世大学接受了HuCNS-SC治疗。关键的是，52%的SCI临床病例发生在宫颈水平。以慢性脊髓损伤人群为目标产生了一个更大的受试者队列，并为临床安全性和有效性评估带来了优势(例如，自发恢复是一个重大的、尖锐的混淆)。对治疗后脊髓损伤改善的辨别部分依赖于自发恢复率。自愈率在急性胸椎病患者中最高，在慢性颈椎病患者中最低。据估计，一项急性胸部脊髓损伤试验需要多达225-250名亚洲A组受试者和1100名亚洲B组受试者才能检测到适度的效果。相比之下，慢性颈椎脊髓损伤试验可能只需要25名亚洲A组受试者和50名亚洲B组受试者。此外，与胸部水平类似的功能增加相比，颈部功能的小幅增加提供了更大比例的生活质量变化。我们利用免疫缺陷的Rag2g/c小鼠建立了单侧颈髓损伤模型，以优化异种移植，并证明了9dpi的HuCNS-SC移植促进了运动功能的恢复，没有不良反应，确立了HuCNS-SC的临床前疗效。UCI-StemCells Inc.的团队在使用HuCNS-SC的临床翻译方面已经拥有了相当多的经验，并以IND前咨询的形式寻求FDA对颈椎SCI适应症的初步反馈。这项建议基于我们FDA的相互作用，旨在扩大我们目前的颈脊髓损伤疗效数据，以评估HuCNS-SC的预期临床细胞批次的有效性和长期安全性/毒理学，旨在解决以下特定目标：目的1：在9dpi移植的单侧颈脊髓损伤小鼠模型中建立HuCNS-SC CCL的有效性和测试细胞输送部位。目的：建立HuCNS-SC CCL在60dpi移植的单侧颈髓损伤小鼠模型中的有效性和细胞输送部位。目的：在自主神经反射障碍大鼠模型上评价HuCNS-SC CCL的安全性。目的：建立单侧颈髓损伤小鼠模型，建立HuCNS-SC CCL的长期安全性/毒理学模型。目标5：如果FDA在第二年的IND前会议上要求，建立HuCNS-SC的有效性和安全性/毒理学 第二个物种(ATN大鼠)的CCL，采用杂交研究设计，颈髓损伤大鼠接受抗唾液酸GM1抗体治疗的补充免疫抑制。该项目的目标将使IND应用于将HuCNS-SC临床细胞批次用于颈椎脊髓损伤 作为治疗的靶点。

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.