Comparative testing of tatCN19o for neuroprotection in rodent tMCAo

tatCN19o 对啮齿动物 tMCAo 神经保护作用的比较测试

• 批准号: 10671969
• 负责人: Olivia Ruth Asfaha
• 金额: $ 29.96万
• 依托单位: NEUREXIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671969
• 关键词: Activase; Acute; Adult; Alteplase; American; Amino Acids; Animals; Blood coagulation; Cell Death; Cerebral Ischemia; Cessation of life; Chemistry; Clinical; Clinical Trials; Coagulation Process; Collaborations; Consensus; Development; Dose; Excision; FDA approved; Family suidae; Filament; Funding; Future; Germ Cells; Health Care Costs; Human; Impaired cognition; Intervention; Ischemia; Ischemic Stroke; Lead; Magnetic Resonance Imaging; Marketing; Mechanics; Middle Cerebral Artery Occlusion; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Operative Surgical Procedures; Parents; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Plasmin; Population; Property; Rattus; Reperfusion Injury; Reporting; Risk; Rodent; Site; Small Business Innovation Research Grant; Standardization; Stimulus; Stroke; Symptoms; Tenecteplase; Testing; Therapeutic; Time; Toxicology; Variant; Water; aged; aortic arch; calmodulin-dependent protein kinase II; cerebroprotection; clinical risk; comparative; efficacy evaluation; excitotoxicity; follow-up; hypertensive; improved; in vivo; in vivo Model; inhibitor; manufacture; model development; mouse model; neuroprotection; participant enrollment; peptide drug; pharmacologic; phase III trial; post stroke; pre-clinical assessment; safety study; severe injury; sex; standard of care; stroke model; stroke risk; stroke therapy

Project Summary/Abstract Focal cerebral ischemia (stroke) afflicts nearly 800,000 Americans each year and often results in permanent cognitive impairment or death. Efforts in developing a cerebroprotective stroke therapy have largely resulted in disappointment: the only approved pharmacological therapy is hemolytic treatment with tissue plasminogen activator (tPA; alteplase). In this project, we will further develop our optimized CaMKII inhibitor peptide tatCN19o as a cerebroprotective stroke treatment through comparative testing within the NINDS Stroke Preclinical Assessment Network (SPAN). The 30 amino-acid peptide is selective, stable, potent, water soluble, and has excellent chemistry, manufacturing, and control (CMC) properties. Importantly, tatCN19o was highly effective in vivo in global cerebral ischemia (GCI) models in both mouse and pig (the latter unpublished), even at extremely low doses of 0.01-0.02 mg/kg i.v.. The parent compound was also effective in vivo in a mouse model of acute ischemic stroke (transient middle cerebral artery occlusion; tMCAo). Neuroprotection was seen even at the latest time points tested so far after the various ischemic/excitotoxic insults (0.5h after global cerebral ischemia; 1h after stroke model; 6h in neuronal cultures). Here, SPAN will provide rigorous, unbiased testing of tatCN19o in rodent tMCAo models for direct comparison to other candidate interventions. Several tMCAo conditions are proposed for consideration by the network: compatibility with hemolytic tPA treatment (the current standard of care) and efficacy after varied insult duration. To most appropriately represent clinical populations, we propose parallel testing in adult and older animals of both sexes.

项目总结/摘要 局灶性脑缺血（中风）每年折磨近80万美国人，并经常导致永久性脑缺血。 认知障碍或死亡。在开发脑卒中保护疗法方面的努力在很大程度上导致了 令人失望的是：唯一批准的药物治疗是用组织纤溶酶原进行溶血治疗， 激活剂（tPA;阿替普酶）。在这个项目中，我们将进一步开发我们优化的CaMKII抑制剂肽 通过NINDS中风内的比较测试，tatCN 19 o作为一种神经保护性中风治疗 临床前评估网络（SPAN）。30个氨基酸的肽是选择性的，稳定的，有效的，水 可溶性，并具有优异的化学、制造和控制（CMC）性能。重要的是，tatCN 19 o 在小鼠和猪（后者）的全脑缺血（GCI）模型中， 未发表），即使在极低剂量0.01-0.02 mg/kg i. v.母体化合物也有效 在急性缺血性中风（短暂性大脑中动脉闭塞; tMCAo）的小鼠模型中体内。 即使在各种缺血/兴奋毒性后的最新时间点，也可以看到神经保护作用。 损伤（全脑缺血后0.5小时;中风模型后1小时;神经元培养物中6小时）。在这里，SPAN将 在啮齿动物tMCAo模型中对tatCN 19 o进行严格、无偏倚的检测，以与其他 候选人干预。提出了几个tMCAo条件供网络考虑： 与溶血性tPA治疗（当前标准治疗）的相容性和各种损伤后的疗效 持续时间为了最恰当地代表临床人群，我们建议在成人和老年人中进行平行测试。 两性的动物。