Calpastatin Peptide-based Calpain Inhibitor as a Traumatic Brain Injury Therapeutic

基于钙蛋白酶肽的钙蛋白酶抑制剂作为创伤性脑损伤的治疗药物

• 批准号: 10002114
• 负责人: JOHN Y ANAGLI
• 金额: $ 26.96万
• 依托单位: NEUROTHERANOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002114
• 关键词: Acute; Acute Brain Injuries; Area; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Chemical Analysis; Blood Pressure; Blood gas; Brain; Brain Injuries; Calcium; Calpain; Caring; Cause of Death; Cell Survival; Cells; Cerebrovascular system; Clinical; Clinical Research; Clinical Treatment; Cognitive; Consumption; Craniocerebral Trauma; Cytoskeletal Proteins; Data; Diffuse Axonal Injury; Direct Costs; Disease; Dose; Drug usage; Edema; Emotional; Enzymes; Event; FDA approved; Facilities and Administrative Costs; Failure; Family suidae; Feasibility Studies; Feedback; Functional disorder; Funding; Future; Generations; Glial Fibrillary Acidic Protein; Glucose; Goals; Growth Associated Protein 43; Head; Health; Health Expenditures; Heart Rate; Hemorrhage; Homeostasis; Hospitalization; Hour; Image; Impaired cognition; Incidence; Injury; Intravenous; Investigation; Ischemia; Knowledge; Laboratories; Lead; Letters; Manufacturer Name; Measurement; Mediating; Medical; Medical Care Costs; Modeling; Natural regeneration; Nature; Neurodegenerative Disorders; Neurologic; Neurons; Neurosurgeon; Outcome; Pathologic; Pathology; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Physiological; Preclinical Drug Development; Proteins; Public Health; Quality of life; Rattus; Research; Rodent Model; Scientist; Secure; Signal Transduction; Small Business Innovation Research Grant; Specificity; Spectrin; Supportive care; Surgeon; TBI Patients; Technology; Temperature; Therapeutic; Therapeutic Human Experimentation; Translational Research; Translations; Trauma; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; base; biomarker panel; brain cell; brain repair; brain tissue; calpain inhibitor; calpastatin; clinical care; cognitive function; cognitive recovery; commercial application; cost; cost outcomes; data submission; disability; drug development; emotional functioning; experience; forced swim test; functional outcomes; improved; in vivo; inhibitor/antagonist; interest; intravenous administration; mild traumatic brain injury; morris water maze; neurological recovery; neurorestoration; novel marker; patient population; peptide drug; pre-clinical; preclinical study; protein TDP-43; receptor; response; standard of care; success; therapy development; transcription factor; traumatic event

Abstract: TBI is a leading cause of death and long-term disability worldwide. Although TBI is a significant medical crisis, there are no FDA-approved pharmacological therapies that have been shown to improve functional outcomes. The long-term goal of this project is to improve the immediate and long-term outcomes of patients inflicted with severe TBI. Successful translation of the therapy to the clinical care of patients with TBI would have an enormous direct impact on function, wellness, and overall quality of life of victims of TBI, while shifting the current clinical treatment paradigm to one that includes a restorative thrust. The product of this SBIR, B27- HYD is an intravenous (IV) peptide drug, used in conjunction with the current standard of care, administered to patients within hours of their suffering a severe TBI. The following two specific aims will be pursued: 1) Determine the dose-response effects of intravenous B27-HYD on a TBI biomarker panel, as well as the drug's effects on general health and physiological measurements in sham and severe TBI rats. Milestone: A safe and effective IV dose of B27- HYD that results in a minimum 40% reduction of 3 out of 5 pharmacodynamic TBI biomarkers (calpain-mediated proteolytic breakdown products of αII-spectrin, GFAP, CRMPs, GAP-43, and TDP-43). Effects of B27-HYD on arterial blood pressure, heart rate, body and head temperature, and blood chemistry (blood gases, glucose) will be determined; and 2) Demonstrate that a safe and effective dose of B27-HYD administered in the correct timeframe protects brain cell and tissue, and improves recovery from cognitive and emotional dysfunction after severe TBI. Milestone: A minimum 35% brain cell and tissue protection, 35% reduction in the sensorimotor deficits (mNSS) and 40% overall improvement in cognitive and emotional deficits (Morris water maze, Elevated Plus Maze, Forced Swimming Test) will be criteria for success to move on to Phase II. As an outcome of the proposed SBIR Phase I investigations, we expect that a safe and effective IV dose of B27-HYD, that significantly reduces TBI biomarkers, will i) increase brain cell survival, ii) enhance brain repair and regeneration, and iii) lead to marked improvement in cognitive and emotional functions. After successful completion of our Phase I feasibility study, we plan to confirm the in vivo efficacy of B27-HYD in a swine model of severe TBI. We have assembled a team of neuroscientists, neurosurgeons, neuroprotective/neurorestorative drug development scientists and regulatory experts with expertise and experience in TBI pathology, preclinical drug development and regulatory experience to pursue the translational research outlined in this proposal.

摘要： 脑外伤是世界范围内导致死亡和长期残疾的主要原因。尽管TBI是一个重要的 医疗危机，目前还没有FDA批准的药物疗法被证明可以 改善功能结果。这个项目的长期目标是改善眼前的 以及重型颅脑损伤患者的长期预后。成功地翻译了 治疗对颅脑损伤患者的临床护理将产生巨大的直接影响 脑外伤患者的功能、健康状况和总体生活质量，同时改变目前的临床 一种包括恢复性推力的治疗模式。这种丁苯橡胶的产品B27- HYD是一种静脉注射(IV)多肽药物，与目前的护理标准结合使用， 在患者遭受严重脑外伤后数小时内给予治疗。以下两个具体内容 将追求的目标：1)确定静脉注射B27-hyd的剂量-反应效应 脑损伤生物标志物小组，以及药物对一般健康和生理的影响 假手术和重型颅脑损伤大鼠的测量。里程碑：安全有效的B27静脉注射剂量- HYD，导致5个药效学TBI生物标志物中的3个至少减少40% (钙蛋白酶介导的αII蛋白分解产物--血影蛋白、胶质纤维酸性蛋白、CRMPs、GAP-43和 TDP-43)。B27-HYD对动脉血压、心率、身体和头部的影响 将测定温度和血液化学指标(血气、血糖)；以及2) 证明安全有效剂量的B27-hyd在正确的 时间框架保护脑细胞和组织，并促进认知和精神障碍的恢复 重型颅脑损伤后的情绪障碍。里程碑：至少35%的脑细胞和组织 保护，感觉运动缺陷(MNSS)减少35%，总体改善40% 认知和情绪障碍(Morris水迷宫、高架加迷宫、强迫游泳 测试)将是成功进入第二阶段的标准。作为拟议的SBIR的结果 I期调查，我们预计安全有效的B27-hyd静脉剂量， 显著减少脑损伤生物标志物，是否会i)增加脑细胞存活率，ii)促进脑修复 和再生，以及iii)导致认知和情感功能的显著改善。 在成功完成第一阶段可行性研究后，我们计划确认体内 B27-HYD在重型颅脑损伤猪模型中的疗效我们已经组建了一支团队 神经科学家、神经外科医生、神经保护/神经恢复药物研发科学家 以及在TBI病理学、临床前药物方面拥有专业知识和经验的监管专家 开发和监管经验，以从事本文件中概述的翻译研究 求婚。