NEUROPROTECTIVE APOLIPOPROTEIN-E ANALOGS

描述（由申请人提供）：创伤性脑损伤（TBI），主要是由于对完整闭合颅骨的撞击，发生在交通事故、福尔斯、暴力行为和体育事故中。TBI是美国死亡和残疾的主要原因，年发病率为150万。其中，5万人急性死亡，23万多人住院，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。目前，没有治疗TBI的疗法已被证明可以改善功能结果，如记忆性能，如果患者存活，这是成功治疗的最重要临床特征。对这种规模的公共卫生问题缺乏治疗干预构成了医疗危机。我们最近已经证明，添加外源性载脂蛋白-E，或从apoE的受体结合域衍生的肽，可以显着降低脑和外周的炎症反应。给予TBI然后在头部损伤后30分钟用COG 133治疗的小鼠表现出更快的恢复时间，并且它们在行为测试上的表现恢复到损伤前水平，而头部损伤盐水治疗的小鼠的行为从未恢复到损伤前的表现水平。在第1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COG 133呈现似乎是抗炎活性所需的两亲性α螺旋结构的模型。超越阶段1，我们已经产生了COG 1410，如本文所公开的显著改性和改进的化合物。在第2阶段，我们提出测试以下假设：三维结构和对特异性蛋白水解降解的抗性将进一步增强所选COG 1410衍生物在TBI、血脑屏障渗透和治疗窗中的活性。这些研究对于获得申报临床前毒理学2B期研究的临床先导药物所需的临床前药理学是必要的，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.