NEUROPROTECTIVE APOLIPOPROTEIN-E ANALOGS

描述（由申请人提供）：创伤性脑损伤（TBI），主要是由于撞击完整的封闭颅骨，发生在车辆事故，跌倒，暴力行为和运动事故中。在美国，脑外伤是导致死亡和残疾的主要原因，年发病率为150万例。其中，5万人急性死亡，23万人住院，8万人长期残疾。创伤性脑损伤影响所有年龄段的人，大多数幸存者患有慢性、终身残疾，并有不同程度的依赖性。目前，还没有一种治疗创伤性脑损伤的疗法被证明可以改善记忆等功能结果，如果患者存活下来，这是治疗成功的最重要的临床特征。对如此严重的公共卫生问题缺乏治疗干预构成了一场卫生保健危机。我们最近已经证明，外源性载脂蛋白e，或从载脂蛋白e受体结合域衍生的肽的添加，可以显著减少大脑和外周的炎症反应。脑外伤后30分钟用COG133治疗的小鼠恢复速度更快，其行为测试的表现恢复到损伤前水平，而脑外伤盐水治疗的小鼠的行为从未恢复到损伤前水平。在第一阶段，我们系统地修饰了apoE 130-150肽化合物，并成功地确定了保留结合和抗炎活性的最小和必需残基。这些数据支持一个模型，即COG 133假设两亲α螺旋结构似乎是抗炎活性所必需的。在第1阶段之后，我们已经创建了COG 1410，这是一种经过显著修饰和改进的化合物，如本文所披露的。在第二阶段，我们提出验证假设，即三维结构和对特定蛋白质水解降解的抵抗力将进一步增强COG1410衍生物在TBI、血脑屏障穿透和治疗窗口方面的活性。这些研究是获得临床前药理学所需的，以宣布临床前毒理学2B期研究的临床先导，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。

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.