Cell Based Therapy for Treatment of Traumatic Brain Injury

治疗创伤性脑损伤的细胞疗法

• 批准号: 8727677
• 负责人: Charles S Cox
• 金额: $ 59.54万
• 依托单位: ATHERSYS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727677
• 关键词: Acute; Address; Adult; Affect; Age; Agreement; American; Anatomy; Animals; Autopsy; Biodistribution; Biotechnology; Blood - brain barrier anatomy; Bone Marrow; Brain Injuries; Cardiovascular Diseases; Catheters; Cell Line; Cell Survival; Cell Therapy; Cells; Cerebral Edema; Cerebrum; Child; Childhood; Choristoma; Clinical Data; Clinical Trials; Critiques; Data; Development; Direct Costs; Disease; Dose; Elderly man; Elderly woman; Environment; Evaluation; Facilities and Administrative Costs; Goals; Healthcare Systems; Hypoxia; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Infusion procedures; Injury; Institutional Review Boards; Intracranial Hypertension; Intracranial Pressure; Intravenous; Investigational Drugs; Ischemic Stroke; Legal patent; Licensing; Life; Link; Literature; Medical; Mesenchymal; Military Personnel; Modeling; Mononuclear; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Nervous System Trauma; Organ; Osmolar Concentration; Outcome; Outcome Measure; Pathology; Patients; Perfusion; Permeability; Pharmacology and Toxicology; Phase; Population; Pre-Clinical Model; Protocols documentation; Publishing; Relative (related person); Research; Research Project Grants; Research Proposals; Rodent; Rodent Model; Safety; Scheme; Secondary to; Signal Transduction; Small Business Innovation Research Grant; Spinal cord injury; Stem cells; Stroke; Supportive care; System; TBI Patients; Texas; Tissues; Toxic effect; Translating; Traumatic Brain Injury; Treatment Protocols; United States; Universities; Walkers; aged; base; cGMP production; cell type; central nervous system injury; clinically relevant; combat; effective therapy; efficacy testing; graft vs host disease; in vivo; injured; male; medical schools; mortality; nervous system disorder; novel therapeutic intervention; pre-clinical; prevent; primary outcome; regenerative; relating to nervous system; response; response to injury; safety study; scale up; secondary outcome; web site

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.

描述(申请人提供)：先前进行和发表的研究表明，Athersys的专利成人黏附干细胞产品MultiStem(R)在创伤性脑损伤(TBI)啮齿动物模型中调节继发性脑损伤的炎症成分。此外，有支持发表的数据说明了多干细胞在其他中枢神经系统损伤模型中的有效性，包括中风、缺氧缺血损伤和脊髓损伤等。Athersys，Inc.和休斯顿的德克萨斯大学医学院达成了一项合作研究协议，以开发体内和体外治疗脑外伤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。这项SBIR快速研究提案的具体目标是确定并成功执行关键的临床前安全性和有效性研究，以成功地向FDA提交新药研究方案，以优化治疗脑外伤及其相关结果的细胞疗法。这项申请建议在第一阶段进行GLP毒性初步研究，然后进行后续研究，以解决神经损伤/疾病的祖细胞治疗中临床相关的翻译问题。具体目标是：第一阶段：通过短期和长期的GLP毒性/病理-尸检评估，确定TBI后静脉注射MultiStem的安全性。建议的研究小组的基本原理是，必须在幼稚和受伤的动物中定义安全性，因为损伤会影响生物分布，继而影响来自受伤组织的化学诱导剂信号。不进行GO的决定将主要基于任何器官中异位组织的发展(不仅仅是细胞的存在)，或者炎症/器官功能的显著恶化。阶段2a：阶段2a的目标是完成全面的脑损伤毒性研究，剂量在我们之前的啮齿动物概念验证疗效测试中被证明是有效的。综合毒性和解剖病理学研究将需要在先前概念验证研究的基础上，在较高剂量/多次剂量下完成。通过评估剂量毒性曲线(与对照相比)与之前的概念验证疗效数据进行比较，将做出去/不去的决定。阶段2b：建议的阶段2b部分的目标是在通过阶段1和阶段2a的安全研究之后，根据主要和次要结果措施建立最佳剂量方案。导管输送系统的翻译问题和细胞输注环境的渗透压将从影响细胞存活和效力的角度进行评估。阶段2c：这一分阶段的主要目标是(1)成人和儿童使用静脉多干细胞治疗重型脑损伤的方案的IND提交，以及(2)针对任何批评处理/修改提交的文件，以及(3)批准和本地IRB提交以允许启动临床试验。

项目成果

Immunomagnetic enrichment and flow cytometric characterization of mouse microglia.

小鼠小胶质细胞的免疫磁富集和流式细胞仪表征。

• DOI: 10.1016/j.jneumeth.2013.07.017
• 发表时间: 2013-09-30
• 期刊: JOURNAL OF NEUROSCIENCE METHODS
• 影响因子: 3
• 作者: Bedi, Supinder S.;Smith, Philippa;Hetz, Robert A.;Xue, Hasen;Cox, Charles S.
• 通讯作者: Cox, Charles S.