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）：脑出血（ICH）是一种毁灭性且相对常见的疾病，仅在美国每年就有多达50,000人受到影响。脑出血仍与预后不良有关，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，与脑出血相关的死亡率几乎没有改善。通过传统的临床前脑出血动物模型、梭状菌胶原酶诱导出血和自体血液注射，越来越多的文献表明，脑出血后特异性丝裂原活化蛋白激酶（MAPK）信号级联和其他信号通路被激活。MAPK蛋白p38、c-Jun n末端激酶（JNK）和细胞外信号相关激酶（ERK）的活化已被报道，这些分子观察结果为开发脑出血新疗法提供了新的方法。载脂蛋白E （apoE）是一种含有299个氨基酸的蛋白质，具有多种生物学特性。除了在胆固醇代谢中的功能外，apoE已被证明在改变中枢神经系统对损伤的反应中起着独特的重要作用，并且在脑出血的情况下，APOE4携带者的药物基因组效应已被证明比APOE3携带者的结果更差。Cognosci最近开发了一种新的基于载脂蛋白的疗法，这种疗法可以穿过血脑屏障，发挥神经保护和抗炎活性。在机制研究中，我们已经证明了COG1410，一个优化的apoE为基础的肽，抑制磷酸化和伴随的MAP激酶的激活，包括p38， JNK和ERK。抑制MAPK激活与减少炎症的观察结果一致，并可能减少脑出血后神经退行性变的发生。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）的兴奋毒性活性，在体外对神经元提供直接的神经保护作用。在围产期缺氧缺血性损伤模型中，神经保护活性也在体内被证实。我们在脑出血胶原酶模型中对COG1410进行了初步评估，发现COG1410通过运动功能和神经严重程度评分来改善预后。基于这些观察结果，我们现在建议测量出血后使用不同剂量的COG1410对神经预后的影响，以确定最佳剂量。此外，我们建议确定COG1410处理对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，这将构成临床前研究的基础，向FDA提交新药研究申请，以启动针对这一重要孤儿症的人体临床试验。公共卫生相关性：脑出血（ICH）是一种破坏性和相对常见的疾病，仅在美国每年就有多达50,000人受到影响。脑出血仍与预后不良有关，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，与脑出血相关的死亡率几乎没有改善。通过传统的临床前脑出血动物模型、梭状菌胶原酶诱导出血和自体血液注射，越来越多的文献表明，脑出血后特异性丝裂原活化蛋白激酶（MAPK）信号级联和其他信号通路被激活。MAPK蛋白p38、c-Jun n末端激酶（JNK）和细胞外信号相关激酶（ERK）的活化已被报道，这些分子观察结果为开发脑出血新疗法提供了新的方法。载脂蛋白E （apoE）是一种含有299个氨基酸的蛋白质，具有多种生物学特性。除了在胆固醇代谢中的功能外，apoE已被证明在改变中枢神经系统对损伤的反应中起着独特的重要作用，并且在脑出血的情况下，APOE4携带者的药物基因组效应已被证明比APOE3携带者的结果更差。Cognosci最近开发了一种新的基于载脂蛋白的疗法，这种疗法可以穿过血脑屏障，发挥神经保护和抗炎活性。在机制研究中，我们已经证明了COG1410，一个优化的apoE为基础的肽，抑制磷酸化和伴随的MAP激酶的激活，包括p38， JNK和ERK。抑制MAPK激活与减少炎症的观察结果一致，并可能减少脑出血后神经退行性变的发生。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）的兴奋毒性活性，在体外对神经元提供直接的神经保护作用。在围产期缺氧缺血性损伤模型中，在体内缺氧后也显示出神经保护活性。我们在脑出血胶原酶模型中对COG1410进行了初步评估，发现COG1410通过运动功能和神经严重程度评分来改善预后。基于这些观察结果，我们现在建议测量出血后使用不同剂量的COG1410对神经预后的影响，以确定最佳剂量。此外，我们建议确定COG1410处理对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，这将构成临床前研究的基础，向FDA提交新药研究申请，以启动针对这一重要孤儿症的人体临床试验。