Novel Therapeutic for SAH

SAH 的新疗法

• 批准号: 7404911
• 负责人: Dale J Christensen
• 金额: $ 24.97万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404911
• 关键词: Accounting; Amino Acids; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein E; Area; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cardiotoxicity; Cause of Death; Cessation of life; Characteristics; Cholesterol Homeostasis; Clinical Trials; Complication; Data; Development; Dose; Early Diagnosis; Elements; Food; Frequencies; Grant; Harvest; Hour; Human; Immunoblotting; In Vitro; Incidence; Industry; Inflammation; Injection of therapeutic agent; Injury; Investigational Drugs; Investigational New Drug Application; Laboratories; Literature; MAPK14 gene; Measures; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; N-Methylaspartate; Necrosis; Neurologic; Neurological outcome; Neurons; Orphan; Oryctolagus cuniculus; Oxygen; Patients; Peptides; Perinatal Hypoxia; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphorylation; Play; Prevention; Principal Investigator; Property; Proteins; Rate; Relative (related person); Reporting; Role; Safety; Signal Pathway; Signal Transduction; Signaling Molecule; Standards of Weights and Measures; Stroke; Subarachnoid Hemorrhage; Survival Rate; Testing; Therapeutic; Toxic effect; Toxicology; United States; United States Food and Drug Administration; Vasospasm; Western Blotting; base; basilar artery; cisterna magna; clinically relevant; day; design; desire; disability; genotoxicity; granulocyte; improved; in vitro Assay; in vitro Model; in vivo; intravenous injection; medical complication; mortality; mouse model; novel; novel strategies; novel therapeutics; oxygen transport; response to injury; stress-activated protein kinase 1; transcription factor

DESCRIPTION: Subarachnoid Hemorrhage (SAH) is a form of stroke that occurs in nearly 40,000 patients each year in the United States. Despite advances in early diagnosis and management, SAH remains a frequent cause of death and disability. In particular, vasospasm is the most common medical complication of subarachnoid hemorrhage, and often leads to further stroke and added death and disability. This disability is the result of ischemic injury due to the lack of oxygen transport to the brain following vasospasm. Although vasospasm remains the most important cause of mortality and neurological morbidity in patients initially surviving aneurismal SAH, no effective treatment has been developed to reduce the frequency of, or to reduce the damage from this complication. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti-inflammatory activities. One of these compounds, COG1410 has been evaluated in a clinically relevant mouse model of SAH increased survival rates, reduced the occurrence of vasospasm and improved neurological outcome (GAO Et Al. 2006, Mesis et al. 2006). We now propose to further evaluate COG1410 for treatment of SAH by determining if the compound will reduce vasospasm in a rabbit model of vasospasm and to investigate a possible mechanism by which this action may occur. We further propose to evaluate COG1410 in two in vitro models to assess genotoxicity and cardiotoxicity. Successful completion of these studies will provide proof of principle that COG1410 has the desired characteristics in inhibition of vasospasm following SAH and that the compound is free from toxic effects that are routinely evaluated using in vitro assays. This proof of principle with then for the basis for initiation of toxicology studies during the Phase II granting period that will be designed to determine the in vivo safety profile for COG1410 so that an Investigational New Drug (IND) application can be filed with the FDA to initiate human clinical trials for this important orphan indication.

描述：蛛网膜下腔出血 (SAH) 是一种中风形式，在美国每年有近 40,000 名患者发生这种情况。尽管早期诊断和治疗取得了进展，SAH 仍然是死亡和残疾的常见原因。特别是，血管痉挛是蛛网膜下腔出血最常见的医学并发症，常常导致进一步的中风并增加死亡和残疾。这种残疾是由于血管痉挛后缺乏向大脑输送氧气而造成的缺血性损伤的结果。尽管血管痉挛仍然是最初幸存的动脉瘤性 SAH 患者死亡和神经系统发病的最重要原因，但尚未开发出有效的治疗方法来减少这种并发症的发生频率或减少其造成的损害。 Cognosci 最近开发了基于 apoE 的新型疗法，可以穿过血脑屏障并发挥神经保护和抗炎活性。其中一种化合物 COG1410 已在临床相关 SAH 小鼠模型中进行了评估，可提高存活率、减少血管痉挛的发生并改善神经系统结果（GAO 等人，2006 年；Mesis 等人，2006 年）。我们现在建议通过确定该化合物是否会减少兔子血管痉挛模型中的血管痉挛来进一步评估 COG1410 对 SAH 的治疗作用，并研究发生这种作用的可能机制。我们进一步建议在两个体外模型中评估 COG1410，以评估遗传毒性和心脏毒性。这些研究的成功完成将提供原理证明，证明 COG1410 具有抑制 SAH 后血管痉挛的所需特性，并且该化合物没有使用体外测定常规评估的毒性作用。这一原则证明将成为第二阶段授权期间启动毒理学研究的基础，该研究旨在确定 COG1410 的体内安全性，以便向 FDA 提交研究性新药 (IND) 申请，启动这一重要孤儿适应症的人体临床试验。