Cell Based Therapy for Treatment of Traumatic Brain Injury

描述（由申请人提供）：先前进行和发表的研究表明，Athersys获得专利的成体贴壁干细胞产品MultiStem(R)可以调节创伤性脑损伤（TBI）啮齿动物模型中继发性脑损伤的炎症成分。此外，也有支持已发表的数据表明MultiStem在其他中枢神经系统损伤模型（包括中风、缺氧缺血性损伤和脊髓损伤等）中的疗效。Athersys, Inc.和德克萨斯大学休斯顿分校医学院签署了一项合作研究协议，用于开发体内和体外治疗TBI和中风的概念验证研究。这种关系的最终目标是将这些初步的积极发现转化为神经损伤的临床试验和新的治疗方法。该SBIR快速通道研究提案的具体目标是定义并成功执行关键的临床前安全性和有效性研究，这些研究是成功向FDA提交研究性新药以优化TBI治疗及其相关结果的细胞治疗方案所必需的。本申请建议在第一阶段进行GLP毒性初步研究，随后进行一系列研究，以解决神经损伤/疾病祖细胞治疗的临床相关转化问题。具体目标如下：第一阶段：通过短期和长期GLP毒性/病理尸检评估，确定TBI后静脉注射MultiStem的安全性。提出分组的基本原理是，必须在初始和受伤的动物中确定安全性，因为受伤影响来自受伤组织的化学引诱剂信号的生物分布。手术的决定将主要基于任何器官的异位组织的发展（不仅仅是细胞的存在），或炎症/器官功能的显著恶化。第2a期：第2a期的目标是完成对TBI的全面毒性研究，我们之前在啮齿动物中进行的概念有效性验证试验显示剂量有效。综合的毒性和解剖病理学研究将需要在先前的概念验证研究的基础上，在更高剂量/多次剂量下完成。将通过评估剂量毒性概况（与对照相比）以及之前的概念验证功效数据来做出GO/NO GO决定。2b期：该提案2b期部分的目标是在通过1期和2a期的安全性研究后，根据主要和次要结果指标建立最佳给药方案。导管输送系统和细胞输注环境的渗透压的转化问题将在影响细胞存活和效力方面进行评估。阶段2c：该子阶段的主要目标是(1)使用静脉注射MultiStem治疗严重TBI的成人和儿童方案的IND提交，(2)针对任何批评意见处理/修改提交，以及(3)批准和当地IRB提交，以允许启动临床试验。

DESCRIPTION (provided by applicant): Previously performed and published studies have demonstrated that MultiStem(R), Athersys' patented adult adherent stem cell product, modulates the inflammatory component of secondary brain injury in rodent models of traumatic brain injury (TBI). Further, there are supporting published data illustrating the efficacy of MultiStem in other CNS injury models including stroke, hypoxic-ischemic injury, and spinal cord injury among others. Athersys, Inc., and the University of Texas Medical School at Houston have a collaborative research agreement in place for the development of proof-of-concept studies in vivo and in vitro for the treatment of TBI and stroke. The ultimate goal of this relationship is to translate these initial positive findings into clinical trials and novel therapeutic approaches for neurological injury. The specific objective of this SBIR Fast-Track Research Proposal is to define and successfully execute pivotal pre-clinical safety and efficacy studies required for a successful Investigational New Drug submission to the FDA for an optimized cellular therapy regimen for treatment of TBI and its related outcomes. This application proposes an initial GLP toxicity study in Phase 1, followed by sequential studies to address clinically relevant translational issues in progenitor cell therapy for neurological injury/disease. The specific aims are: Phase 1: Define the safety profile of MultiStem delivered intravenously after TBI with both short and long-term GLP toxicity/pathology-necropsy evaluation. The rationale for the proposed groups is that safety must be defined in naive and injured animals, since injury affects biodistribution secondary to chemo-attractant signals from injured tissues. NO GO decision will be based principally on the development of ectopic tissue in any organ (not just cell presence), or significant exacerbation of inflammation/organ function. Phase 2a: The goal of Phase 2a is the completion of comprehensive toxicity studies in TBI, with doses shown to be efficacious in our previous proof-of-concept efficacy testing in rodents. Comprehensive toxicity and anatomic pathology studies will need to be completed at higher doses/multiple doses based on previous proof- of-concept studies. GO/NO GO decisions will be made by assessing the dose toxicity profiles (compared to Controls) relative to previous proof-of-concept efficacy data. Phase 2b: The goal of the Phase 2b portion of the proposal is to establish the optimal dosing scheme based on primary and secondary outcomes measures, after clearing safety studies in Phase 1 and Phase 2a. Translational issues of catheter delivery systems and osmolarity of the cell infusion environment will be evaluated in terms of affecting cell survival and potency. Phase 2c: The primary goals of this sub-phase are (1) IND submission for both adult and pediatric protocols using intravenous MultiStem for severe TBI, and (2) addressing/revising the submissions in response to any critiques, and (3) approval and local IRB submission to allow initiation of the clinical trials.