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: 8252522
• 负责人: Charles S Cox
• 金额: $ 30万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252522
• 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（由申请人提供）： 先前进行并发表的研究表明，Athersys 的专利成体贴壁干细胞产品 MultiStem® 可调节创伤性脑损伤 (TBI) 啮齿动物模型中继发性脑损伤的炎症成分。此外，已发表的支持数据说明了 MultiStem 在其他中枢神经系统损伤模型中的功效，包括中风、缺氧缺血性损伤和脊髓损伤等。 Athersys, Inc. 和休斯敦德克萨斯大学医学院签订了一项合作研究协议，用于开发治疗 TBI 和中风的体内和体外概念验证研究。这种关系的最终目标是将这些最初的积极发现转化为临床试验和神经损伤的新治疗方法。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，以便成功向 FDA 提交研究性新药，以优化治疗 TBI 及其相关结果的细胞治疗方案。该申请建议在第一阶段进行初步 GLP 毒性研究，随后进行连续研究，以解决神经损伤/疾病的祖细胞治疗中的临床相关转化问题。具体目标是： 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。拟议组的基本原理是，必须在幼稚和受伤的动物中定义安全性，因为损伤影响继发于受伤组织的化学引诱信号的生物分布。否 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），或炎症/器官功能的显着恶化。 2a 期：2a 期的目标是完成 TBI 的综合毒性研究，在我们之前的啮齿类动物概念验证功效测试中，剂量被证明是有效的。根据之前的概念验证研究，需要以更高剂量/多次剂量完成全面的毒性和解剖病理学研究。将通过评估相对于之前的概念验证功效数据的剂量毒性特征（与对照相比）来做出继续/不继续的决定。第 2b 阶段：该提案第 2b 阶段部分的目标是在完成第 1 阶段和第 2a 阶段的安全性研究后，根据主要和次要结果指标建立最佳剂量方案。导管输送系统的转化问题和细胞输注环境的渗透压将根据对细胞存活和效力的影响进行评估。 2c 阶段：该子阶段的主要目标是 (1) 提交使用静脉 MultiStem 治疗严重 TBI 的成人和儿童方案的 IND，以及 (2) 针对任何批评处理/修改提交内容，以及 (3) 批准并提交当地 IRB，以允许启动临床试验。