Therapeutic for Intracerebral Hemorrhage

描述（由申请人提供）：脑出血（ICH）是一种毁灭性的和相对常见的疾病，仅在美国每年就影响多达50，000人。ICH仍然与不良结局相关，大约40%至50%的患者将在30天内死亡。不幸的是，在过去的20年里，ICH相关的死亡率几乎没有改善。使用传统的临床前ICH动物模型，梭菌胶原酶诱导的出血和自体血液注射，越来越多的文献表明，特定的丝裂原活化蛋白激酶（MAPK）信号级联和其他信号通路在ICH后被激活。已经报道了MAPK蛋白p38、c-Jun N-末端激酶（JNK）和细胞外信号相关激酶（ERK）的激活，这些分子观察结果表明可以开发用于ICH新疗法的新方法。载脂蛋白E（apoE）是一种由299个氨基酸组成的具有多种生物学特性的蛋白质。除了其在胆固醇代谢中的功能外，已证明apoE在改变CNS对损伤的反应中发挥独特的重要作用，并且在ICH的情况下，已证明药物基因组学效应，其中APOE 4载体相对于其APOE 3对应物遭受更差的结果。Cognosci最近开发了新的基于apoE的治疗剂，其穿过血脑屏障并发挥神经保护和抗炎活性。在机制研究中，我们已经证明了COG 1410（一种优化的基于apoE的肽）抑制磷酸化和伴随的MAP激酶（包括p38、JNK和ERK）的活化。MAPK活化的抑制与炎症减少的观察结果一致，并可能减少ICH后神经变性的发生。此外，我们已经证明，apoE模拟肽提供直接的神经元保护作用，在体外通过抑制兴奋毒性活性的N-甲基-D-天冬氨酸（NMDA）。在围产期缺氧缺血性损伤模型中，缺氧后体内也表现出神经保护活性。我们在ICH的胶原酶模型中对COG 1410进行了初步评估，发现COG 1410改善了运动功能和神经严重性评分的结果。基于这些观察结果，我们现在建议测量出血后给予不同剂量的COG 1410对神经系统结局的影响，以确定最佳剂量。此外，我们建议确定COG 1410治疗对ICH后关键MAPK信号转导蛋白磷酸化状态的影响。通过完成这项工作，我们将获得原理证明，这将成为向FDA提交研究性新药申请所需的临床前研究的基础，以启动这一重要孤儿适应症的人体临床试验。公共卫生相关性：脑出血（ICH）是一种毁灭性的和相对常见的疾病，仅在美国每年就影响多达50，000人。ICH仍然与不良结局相关，大约40%至50%的患者将在30天内死亡。不幸的是，在过去的20年里，ICH相关的死亡率几乎没有改善。使用传统的临床前ICH动物模型，梭菌胶原酶诱导的出血和自体血液注射，越来越多的文献表明，特定的丝裂原活化蛋白激酶（MAPK）信号级联和其他信号通路在ICH后被激活。已经报道了MAPK蛋白p38、c-Jun N-末端激酶（JNK）和细胞外信号相关激酶（ERK）的激活，这些分子观察结果表明可以开发用于ICH新疗法的新方法。载脂蛋白E（apoE）是一种由299个氨基酸组成的具有多种生物学特性的蛋白质。除了其在胆固醇代谢中的功能外，已证明apoE在改变CNS对损伤的反应中发挥独特的重要作用，并且在ICH的情况下，已证明药物基因组学效应，其中APOE 4载体相对于其APOE 3对应物遭受更差的结果。Cognosci最近开发了新的基于apoE的治疗剂，其穿过血脑屏障并发挥神经保护和抗炎活性。在机制研究中，我们已经证明了COG 1410（一种优化的基于apoE的肽）抑制磷酸化和伴随的MAP激酶（包括p38、JNK和ERK）的活化。MAPK活化的抑制与炎症减少的观察结果一致，并可能减少ICH后神经变性的发生。此外，我们已经证明，apoE模拟肽提供直接的神经元保护作用，在体外通过抑制兴奋毒性活性的N-甲基-D-天冬氨酸（NMDA）。在围产期缺氧缺血性损伤模型中，缺氧后体内也证明了神经保护活性。我们在ICH的胶原酶模型中对COG 1410进行了初步评估，发现COG 1410改善了运动功能和神经严重性评分的结果。基于这些观察结果，我们现在建议测量出血后给予不同剂量的COG 1410对神经系统结局的影响，以确定最佳剂量。此外，我们建议确定COG 1410治疗对ICH后关键MAPK信号转导蛋白磷酸化状态的影响。通过完成这项工作，我们将获得原理证明，这将成为向FDA提交研究性新药申请所需的临床前研究的基础，以启动这一重要孤儿适应症的人体临床试验。

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating and relatively common disease affecting as many as 50,000 people annually in the United States alone. ICH remains associated with poor outcome, and approximately 40 to 50% of afflicted patients will die within 30 days. Unfortunately, little improvement has been made in the ICH associated mortality rate over the last 20 years. Using the traditional preclinical ICH animals models, clostridial collagenase-induced hemorrhage and autologous blood injection, a growing body of literature indicates that specific mitogen activated protein kinase (MAPK) signaling cascades and other signaling pathways become activated following ICH. Activation of the MAPK proteins p38, c-Jun N-terminal Kinase (JNK), and Extracellular signal-Related Kinase (ERK) have been reported and these molecular observations suggest new approaches that can be exploited for development of novel therapies for ICH. Apoliopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its function in cholesterol metabolism, apoE has been demonstrated to play a uniquely important role in modifying the CNS response to injury, and in the case of ICH, a pharmacogenomic effect has been demonstrated where APOE4 carriers suffer worse outcome relative to their APOE3 counterparts. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti- inflammatory activities. In mechanistic studies we have demonstrated that COG1410, an optimized apoE- based peptide, suppresses phosphorylation and the accompanying activation of MAP kinases including p38, JNK, and ERK. Suppression of MAPK activation is consistent with the observation of reduced inflammation and may reduce the occurrence of neurodegeneration following ICH. Furthermore, we have demonstrated that apoE-mimetic peptides provide direct neuroprotective effects on neurons in vitro by inhibiting the excitotoxic activity of N-Methyl-D-Aspartate (NMDA). Neuroprotective activity was also demonstrated in vivo following oxygen depravation in a perinatal hypoxia model of ischemic injury. We performed an initial evaluation of COG1410 in the collagenase model of ICH and found that COG1410 improved outcome as measured by motor function and neuroseverity scores. Based on these observations, we now propose to measure the effect of different doses of COG1410, administered after the hemorrhage, on neurological outcome to determine the optimal dose. Further, we propose to determine the effect of COG1410 treatment on the phosphorylation status of key MAPK signal transduction proteins following ICH. By completing this work we will obtain proof of principle that will form the basis for preclinical studies required to file an Investigational New Drug application with the FDA to initiate human clinical trials for this important orphan indication. PUBLIC HEALTH RELEVANCE: Intracerebral hemorrhage (ICH) is a devastating and relatively common disease affecting as many as 50,000 people annually in the United States alone. ICH remains associated with poor outcome, and approximately 40 to 50% of afflicted patients will die within 30 days. Unfortunately, little improvement has been made in the ICH associated mortality rate over the last 20 years. Using the traditional preclinical ICH animals models, clostridial collagenase-induced hemorrhage and autologous blood injection, a growing body of literature indicates that specific mitogen activated protein kinase (MAPK) signaling cascades and other signaling pathways become activated following ICH. Activation of the MAPK proteins p38, c-Jun N-terminal Kinase (JNK), and Extracellular signal-Related Kinase (ERK) have been reported and these molecular observations suggest new approaches that can be exploited for development of novel therapies for ICH. Apoliopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its function in cholesterol metabolism, apoE has been demonstrated to play a uniquely important role in modifying the CNS response to injury, and in the case of ICH, a pharmacogenomic effect has been demonstrated where APOE4 carriers suffer worse outcome relative to their APOE3 counterparts. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti- inflammatory activities. In mechanistic studies we have demonstrated that COG1410, an optimized apoE- based peptide, suppresses phosphorylation and the accompanying activation of MAP kinases including p38, JNK, and ERK. Suppression of MAPK activation is consistent with the observation of reduced inflammation and may reduce the occurrence of neurodegeneration following ICH. Furthermore, we have demonstrated that apoE-mimetic peptides provide direct neuroprotective effects on neurons in vitro by inhibiting the excitotoxic activity of N-Methyl-D-Aspartate (NMDA). Neuroprotective activity was also demonstrated in vivo following oxygen deprivation in a perinatal hypoxia model of ischemic injury. We performed an initial evaluation of COG1410 in the collagenase model of ICH and found that COG1410 improved outcome as measured by motor function and neuroseverity scores. Based on these observations, we now propose to measure the effect of different doses of COG1410, administered after the hemorrhage, on neurological outcome to determine the optimal dose. Further, we propose to determine the effect of COG1410 treatment on the phosphorylation status of key MAPK signal transduction proteins following ICH. By completing this work we will obtain proof of principle that will form the basis for preclinical studies required to file an Investigational New Drug application with the FDA to initiate human clinical trials for this important orphan indication.