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) 是一种破坏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。 ICH 仍然与不良预后相关，大约 40% 至 50% 的患者将在 30 天内死亡。不幸的是，过去 20 年来 ICH 相关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注射，越来越多的文献表明特定的丝裂原激活蛋白激酶 (MAPK) 信号级联和其他信号通路在 ICH 后被激活。 MAPK 蛋白 p38、c-Jun N 末端激酶 (JNK) 和细胞外信号相关激酶 (ERK) 的激活已被报道，这些分子观察结果表明可用于开发 ICH 新疗法的新方法。载脂蛋白 E (apoE) 是一种 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方面发挥着独特的重要作用，并且在 ICH 的情况下，已证明药物基因组效应使 APOE4 携带者相对于 APOE3 遭受更差的结果同行。 Cognosci 最近开发了新型基于 apoE 的疗法，可以穿过血脑屏障并发挥神经保护和抗炎活性。在机制研究中，我们证明 COG1410（一种优化的基于 apoE 的肽）可抑制磷酸化以及随之而来的 MAP 激酶（包括 p38、JNK 和 ERK）的激活。 MAPK 激活的抑制与炎症减少的观察结果一致，并且可能减少 ICH 后神经变性的发生。此外，我们还证明，apoE 模拟肽通过抑制 N-甲基-D-天冬氨酸 (NMDA) 的兴奋性毒性活性，在体外对神经元提供直接的神经保护作用。在缺血性损伤的围产期缺氧模型中，缺氧后的体内神经保护活性也得到了证实。我们在 ICH 胶原酶模型中对 COG1410 进行了初步评估，发现 COG1410 改善了运动功能和神经严重程度评分的结果。基于这些观察结果，我们现在建议测量出血后施用的不同剂量的 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 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，我们将获得原则证明，该证明将构成向 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。 ICH 仍然与不良预后相关，大约 40% 至 50% 的患者将在 30 天内死亡。不幸的是，过去 20 年来 ICH 相关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注射，越来越多的文献表明特定的丝裂原激活蛋白激酶 (MAPK) 信号级联和其他信号通路在 ICH 后被激活。 MAPK 蛋白 p38、c-Jun N 末端激酶 (JNK) 和细胞外信号相关激酶 (ERK) 的激活已被报道，这些分子观察结果表明可用于开发 ICH 新疗法的新方法。载脂蛋白 E (apoE) 是一种 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方面发挥着独特的重要作用，并且在 ICH 的情况下，已证明药物基因组效应使 APOE4 携带者相对于 APOE3 遭受更差的结果同行。 Cognosci 最近开发了新型基于 apoE 的疗法，可以穿过血脑屏障并发挥神经保护和抗炎活性。在机制研究中，我们证明 COG1410（一种优化的基于 apoE 的肽）可抑制磷酸化以及随之而来的 MAP 激酶（包括 p38、JNK 和 ERK）的激活。 MAPK 激活的抑制与炎症减少的观察结果一致，并且可能减少 ICH 后神经变性的发生。此外，我们还证明，apoE 模拟肽通过抑制 N-甲基-D-天冬氨酸 (NMDA) 的兴奋性毒性活性，在体外对神经元提供直接的神经保护作用。在缺血性损伤的围产期缺氧模型中，缺氧后的体内神经保护活性也得到了证实。我们在 ICH 胶原酶模型中对 COG1410 进行了初步评估，发现 COG1410 改善了运动功能和神经严重程度评分的结果。基于这些观察结果，我们现在建议测量出血后施用的不同剂量的 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 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，我们将获得原则证明，该证明将构成向 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。