NEUROPROTECTIVE APOLIPOPROTEIN-E ANALOGS

神经保护载脂蛋白-E 类似物

基本信息

批准号：
7276561
负责人：
MICHAEL PETER VITEK
金额：
$ 34.61万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-15 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7276561
关键词：
Accidents Address Affect Age Alanine American Amino Acids Amphipathic Alpha Helix Animals Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Apolipoproteins Behavior Behavioral Binding Biological Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cause of Death Cells Characteristics Chemicals Chronic Clinical Clinical Trials Craniocerebral Trauma Data Dependence Development Drug Design Drug Kinetics Endopeptidases Excision Exhibits Funding Future Glutamates Goals Grant Half-Life Hand Head Healthcare Human In Vitro Incidence Industry Inflammation Inflammatory Inflammatory Response Injury Investigational Drugs Investigational New Drug Application LDL-Receptor Related Protein 1 Lead Life Maps Maximum Tolerated Dose Measurement Measures Memory Metabolic Modeling Modification Motor Activity Mus Neuraxis New Drug Approval Process Numbers Patients Penetration Peptide Hydrolases Peptides Performance Permeability Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Plasma Progress Reports Property Proteolysis Public Health Publishing Rate Reactive Oxygen Species Reading Recovery Relative (related person)Research Research Personnel Resistance Safety Saline Scanning Screening procedure Site Small Business Funding Mechanisms Small Business Innovation Research Grant Sports Structure Structure-Activity Relationship Survivors Testing Therapeutic Therapeutic Agents Therapeutic Index Therapeutic Intervention Time Toxic effect Toxicology Trauma Traumatic Brain Injury United States United States Food and Drug Administration Violence Work alpha helix analog base behavior test cognitive function cranium cytokine design disability drug development experience falls functional outcomes improved in vivo injured mimetics mortality mouse model novel pre-clinical preclinical study programs receptor binding research study response to injury small molecule three dimensional structure uptake

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI), principally as a result of impaction on the intact closed skull, occurs in vehicular incidents, falls, acts of violence, and sports accidents. TBI is the leading cause of death and disability in the United States, with an annual incidence rate of 1.5 million. Of these, 50,000 die acutely, over 230,000 are hospitalized, and 80,000 experience long term disability. TBI affects people of all ages with most survivors suffering chronic, life-long disabilities with varying degrees of dependence. Currently, there are no therapies to treat TBI that have been demonstrated to improve functional outcomes like memory performance, which if the patient survives, is the most important clinical characteristic of a successful therapy. The lack of therapeutic intervention for a public health issue of this magnitude constitutes a healthcare crisis. We have recently demonstrated that the addition of exogenous apolipoprotein-E, or peptides derived from apoE's receptor binding domain, can significantly reduce inflammatory responses in the brain and in the periphery. Mice given TBI and then treated with COG133 at 30 minutes following head injury exhibited faster recovery times and their performance on behavioral tests recovered to pre-injury levels, whereas the behavior of head-injured saline treated mice never returned to preinjury levels of performance. In Phase 1 we systematically modified the apoE 130-150 peptide compound and successfully defined the minimal and essential residues that retain binding and anti-inflammatory activities. These data support a model where COG 133 assumes the structure of an amphipathic alpha helix that appears to be required for anti-inflammatory activity. Going beyond Phase 1, we have created COG 1410, a significantly modified and improved compound as disclosed herein. In Phase 2, we propose to test the hypothesis that the 3- dimensional structure and resistance to specific proteolytic degradation will further enhance activity in TBI, blood brain barrier penetration and therapeutic window of selected derivatives of COG1410. These studies are necessary to acquire the pre-clinical pharmacology needed to declare a clinical lead for Phase 2B studies of pre-clinical toxicology to support an IND application and Phase 3 human clinical trial studies to support an NDA application with the FDA.

描述（由申请人提供）：创伤性脑损伤 (TBI)，主要是由于完整闭合的头骨受到撞击造成的，发生在交通事故、跌倒、暴力行为和运动事故中。 TBI 是美国死亡和残疾的主要原因，年发病率为 150 万人。其中，50,000 人急性死亡，超过 230,000 人住院治疗，80,000 人长期残疾。 TBI 影响所有年龄段的人，大多数幸存者患有慢性、终身残疾并具有不同程度的依赖。目前，尚无治疗 TBI 的疗法被证明可以改善记忆表现等功能结果，如果患者存活下来，记忆表现是成功治疗的最重要的临床特征。对于如此严重的公共卫生问题缺乏治疗干预构成了医疗危机。我们最近证明，添加外源载脂蛋白-E，或源自apoE受体结合域的肽，可以显着减少大脑和外周的炎症反应。头部受伤后 30 分钟接受 TBI 并随后接受 COG133 治疗的小鼠表现出更快的恢复时间，并且它们在行为测试中的表现恢复到受伤前的水平，而头部受伤盐水治疗的小鼠的行为从未恢复到受伤前的表现水平。在第一阶段，我们系统地修饰了 apoE 130-150 肽化合物，并成功定义了保留结合和抗炎活性的最小和必需的残基。这些数据支持一个模型，其中 COG 133 呈现两亲性 α 螺旋结构，这似乎是抗炎活性所必需的。超越第一阶段，我们已经创建了 COG 1410，这是一种如本文所公开的显着修改和改进的化合物。在第 2 阶段，我们建议测试以下假设：3 维结构和对特定蛋白水解降解的抵抗力将进一步增强 COG1410 选定衍生物的 TBI 活性、血脑屏障穿透性和治疗窗。这些研究对于获得临床前药理学是必要的，以声明临床前毒理学 2B 期研究的临床领先地位，以支持 IND 申请和 3 期人体临床试验研究，以支持 FDA 的 NDA 申请。