Therapeutic for Intracerebral Hemorrhage

脑出血的治疗

• 批准号: 7741461
• 负责人: Dale J Christensen
• 金额: $ 25.86万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741461
• 关键词: Address; Affect; American Heart Association; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein E; Autologous; Basal Ganglia; Biological; Blood; Blood - brain barrier anatomy; Brain; Brain hemorrhage; Cerebral hemisphere hemorrhage; Characteristics; Cholesterol Homeostasis; Clinical; Clinical Trials; Data; Development; Disease; Dose; Edema; Evaluation; Extracellular Signal Regulated Kinases; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genotype; Grant; Guidelines; Hematoma; Hemorrhage; Histologic; Hour; Human; Immunoblotting; In Vitro; Inflammation; Injection of therapeutic agent; Injury; Investigational New Drug Application; Left; Literature; MAPK14 gene; Measures; Mitogen-Activated Protein Kinases; Modeling; Molecular; Motor; Mus; N-Methylaspartate; Nerve Degeneration; Neurological outcome; Neurons; Orphan; Outcome; Oxygen; Patients; Peptides; Performance; Perinatal Hypoxia; Pharmacogenomics; Phase; Phase I Clinical Trials; Phosphorylation; Play; Principal Investigator; Property; Proteins; Recovery; Relative (related person); Reporting; Rodent; Role; Safety; Signal Pathway; Signal Transduction; Signaling Molecule; Subarachnoid Hemorrhage; Testing; Therapeutic; Time; Tissues; Toxicology; Transgenic Mice; United States; United States National Institutes of Health; Western Blotting; Work; abstracting; apolipoprotein E-3; apolipoprotein E-4; base; clinically relevant; collagenase; deprivation; design; follow-up; improved; in vivo; intravenous injection; mimetics; mortality; mouse model; neuromuscular function; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical study; public health relevance; response; response to injury; stress-activated protein kinase 1

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.

描述（由申请人提供）：脑内出血（ICH）是一种毁灭性且相对常见的疾病，仅在美国，每年都会影响多达50,000人。 ICH仍然与不良预后有关，大约40％至50％的患者将在30天内死亡。不幸的是，在过去20年中，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，梭菌酶诱导的出血和自体注射，越来越多的文献表明，特定的有丝分裂原活化蛋白激酶（MAPK）信号级联和其他信号传导途径在ICH后激活。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，这些分子观察表明，可以利用可利用的新方法来开发ICH的新型疗法。载脂蛋白E（APOE）是具有多种生物学特性的299个氨基酸蛋白。除了其在胆固醇代谢中的功能外，APOE还被证明在改变CNS对损伤的反应中起着独特的重要作用，就ICH而言，已经证明了APOE4载体相对于其APOE3对应物的结果较差的药物基因组效应。 Cognosci最近开发了新型的基于APOE的治疗剂，这些治疗疗法越过血脑屏障并发挥神经保护作用和抗炎活性。在机械研究中，我们已经证明了一种优化的基于APOE的肽COG1410抑制了磷酸化和随附的MAP激酶的激活，包括p38，JNK和ERK。 MAPK激活的抑制与观察到减少炎症的观察，并可能减少ICH后神经退行性的发生。此外，我们已经证明，APOE模拟肽通过抑制N-甲基-D-天冬氨酸（NMDA）的兴奋性活性对神经元的直接神经保护作用。在围产期缺血性损伤模型中氧气衰减后，还显示了神经保护活性。我们在ICH的胶原酶模型中对COG1410进行了初步评估，发现COG1410改善了通过运动功能和神经胶质性得分来衡量的结果。基于这些观察结果，我们现在建议测量出血后给药的不同剂量的COG1410对神经系统结果的影响，以确定最佳剂量。此外，我们建议确定COG1410治疗对ICH之后关键MAPK信号转导蛋白的磷酸化状态的影响。通过完成这项工作，我们将获得原理证明，该证明将构成向FDA提交研究新药应用所需的临床前研究的基础，以启动人类的临床试验，以实现这一重要的孤儿指示。公共卫生相关性：脑内出血（ICH）是一种毁灭性且相对常见的疾病，仅在美国，每年都会影响多达50,000人。 ICH仍然与不良预后有关，大约40％至50％的患者将在30天内死亡。不幸的是，在过去20年中，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，梭菌酶诱导的出血和自体注射，越来越多的文献表明，特定的有丝分裂原活化蛋白激酶（MAPK）信号级联和其他信号传导途径在ICH后激活。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，这些分子观察表明，可以利用可利用的新方法来开发ICH的新型疗法。载脂蛋白E（APOE）是具有多种生物学特性的299个氨基酸蛋白。除了其在胆固醇代谢中的功能外，APOE还被证明在改变CNS对损伤的反应中起着独特的重要作用，就ICH而言，已经证明了APOE4载体相对于其APOE3对应物的结果较差的药物基因组效应。 Cognosci最近开发了新型的基于APOE的治疗剂，这些治疗疗法越过血脑屏障并发挥神经保护作用和抗炎活性。在机械研究中，我们已经证明了一种优化的基于APOE的肽COG1410抑制了磷酸化和随附的MAP激酶的激活，包括p38，JNK和ERK。 MAPK激活的抑制与观察到减少炎症的观察，并可能减少ICH后神经退行性的发生。此外，我们已经证明，APOE模拟肽通过抑制N-甲基-D-天冬氨酸（NMDA）的兴奋性活性对神经元的直接神经保护作用。在围产期缺血性损伤模型中，在体内还显示了神经保护活性。我们在ICH的胶原酶模型中对COG1410进行了初步评估，发现COG1410改善了通过运动功能和神经胶质性得分来衡量的结果。基于这些观察结果，我们现在建议测量出血后给药的不同剂量的COG1410对神经系统结果的影响，以确定最佳剂量。此外，我们建议确定COG1410治疗对ICH之后关键MAPK信号转导蛋白的磷酸化状态的影响。通过完成这项工作，我们将获得原理证明，该证明将构成向FDA提交研究新药应用所需的临床前研究的基础，以启动人类的临床试验，以实现这一重要的孤儿指示。