Stroke Preclicinal Assessment Network

中风临床前评估网络

• 批准号: 10591199
• 负责人: Cenk Ayata
• 金额: $ 66.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591199
• 关键词: Acute; Advocate; Animal Experimentation; Animal Model; Animals; Blinded; Cerebral Ischemia; Charge; Chronic; Clinical; Clinical Trials; Common Data Element; Complement; Data; Edema; Ensure; Event; Filament; Hemorrhage; Histologic; Human Resources; Hyperglycemic Mice; Image; Imaging Device; Inbred SHR Rats; Intervention; Ischemic Stroke; Laboratories; Lead; Magnetic Resonance Imaging; Manuscripts; Middle Cerebral Artery Occlusion; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurocognitive; Neurologic; Neurological outcome; Obese Mice; Outcome Assessment; Peer Review; Physiological; Preclinical Testing; Protocols documentation; Publishing; Randomized; Rattus; Reperfusion Therapy; Reproducibility; Research; Resources; Rest; Rodent; Safety; Scientist; Stroke; Structure; Testing; Therapeutic; Tissues; Video Recording; Weather; Wild Type Mouse; Work; acute stroke; analysis pipeline; animal data; automated analysis; blood-brain barrier disruption; central database; cerebroprotection; clinical candidate; clinical predictors; clinically relevant; design; diet-induced obesity; experience; follow-up; functional outcomes; high standard; indexing; innovation; molecular marker; mortality; optical imaging; pandemic disease; pre-clinical; pre-clinical assessment; preclinical study; preclinical trial; prospective; recruit; resilience; response; stroke intervention; stroke therapy; success; therapy development; tool; tractography; treatment effect; vasogenic edema

Exploratory animal data on potential stroke therapies has not been predictive of clinical success. There are concerns over the design and conduct of pre-clinical studies, their reproducibility and generalizability. The response to this challenge was the NINDS Stroke Preclinical Assessment Network (SPAN), an unbiased multicenter platform for preclinical confirmatory studies in translational stroke research. The MGH team was among the six laboratories selected by the peer review for this first iteration of SPAN (SPAN-1). We made major contributions to the design of SPAN-1. MGH took charge of the MRI protocol for SPAN-1 and helped develop a fully automated analysis pipeline. We then contributed almost 400 animals in under 2 years to test six different acute stroke interventions. Each animal underwent two MRIs (days 2 and 30) and two neurological tests (days 7 and 28). Overall mortality was only ~10% during 28-day survival. Our technical losses amounted to just 17 animals. There were only 3 protocol deviations or violations. Our overarching aim is to repeat this success in the next iteration of SPAN (SPAN-2). We are an experienced team of clinical and basic scientists capable of adjusting to the needs of the network. MGH SPAN team has collectively published over 100 manuscripts using various focal cerebral ischemia models and acute and chronic neurological outcome readouts in rodents. MGH will also bring additional innovative approaches to SPAN-2, such as introducing MRI readouts for hemorrhagic transformation, blood-brain barrier (BBB) disruption and tractography. We will complement the latter with optical imaging of resting state functional connectivity (RSFC) at the end of the follow up period. Aim 1. Contribute to SPAN-2 as a testing laboratory. We pledge to repeat our success in SPAN-1, working as a team with the rest of the network and sustaining our high standards with built-in redundancies to ensure our resilience in the face of personnel changes and disruptive events such as pandemics and weather. Aim 2. Introduce innovative new structural and functional indices to enrich the SPAN readouts. We will go beyond recruiting subjects for the trial by introducing innovative readouts such as hemorrhage, edema, structural and functional connectivity, and histological analyses, which have not been part of SPAN-1. Aim 3. Test whether an unbiased, multicenter, randomized, and blinded preclinical trial network can confirm or refute the published exploratory efficacy and safety data. We hypothesize that SPAN will have the statistical power and an unbiased structure to provide conclusive evidence confirming or refuting published exploratory data of prospective cerebroprotective therapies in ischemic stroke in combination with reperfusion. For over a decade, we have advocated for and passionately supported the concept of an unbiased multicenter preclinical testing platform. We enthusiastically worked as part of SPAN-1 to ensure its success. And now we are fully committed to support SPAN-2 to make it a success as well.

有关潜在中风疗法的探索性动物数据尚未预测临床成功。那里 是对临床前研究的设计和行为的关注，它们的可重复性和可推广性。这 对这一挑战的反应是Ninds Stroke临床前评估网络（SPAN），这是无偏见的 翻译中风研究中临床前验证研究的多中心平台。 MGH团队是 在同行评审选择的六个实验室中，第一次跨越跨度（SPAN-1）。 我们为SPAN-1的设计做出了重大贡献。 MGH负责MRI协议 SPAN-1并帮助开发了完全自动化的分析管道。然后，我们在 2年以下测试六种不同的急性中风干预措施。每只动物接受了两个MRI（第2和30天） 以及两个神经系统测试（第7和28天）。在28天生存期间，总体死亡率仅为10％。我们的 技术损失仅为17只动物。只有3个协议偏差或违规行为。我们的 总体目的是在SPAN（SPAN-2）的下一次迭代中重复这一成功。 我们是一支经验丰富的临床和基础科学家团队，能够适应 网络。 MGH SPAN团队已使用各种局灶性大脑共同出版了100多本手稿 啮齿动物中的缺血模型以及急性和慢性神经系统结局读数。 MGH也会带来 SPAN-2的其他创新方法，例如引入出血的MRI读数 转化，血脑屏障（BBB）破坏和拖拉术。我们将与后者补充 随访期结束时静止状态功能连接性（RSFC）的光学成像。 AIM 1。为SPAN-2作为测试实验室做出贡献。我们保证在Span-1中重复我们的成功， 与其他网络的团队合作，并通过内置冗余来维持我们的高标准 面对人事变化和破坏性事件，例如大流行和天气，请确保我们的韧性。 目标2。引入创新的新结构和功能指标，以丰富跨度读数。我们将 通过引入出血，水肿，等创新读数，超越招聘主题进行试验。 结构和功能连通性以及组织学分析，这些分析不是SPAN-1的一部分。 目标3。测试一个公正，多中心，随机和盲目的临床前试验网络是否可以 确认或驳斥已发表的探索功效和安全数据。我们假设跨度将具有 统计能力和公正的结构，以提供确认或反驳已发表的确定证据 缺血性中风中前瞻性脑保护疗法与再灌注相结合的探索数据。 十多年来，我们一直倡导并热情地支持了公正的概念 多中心临床前测试平台。我们热情地作为SPAN-1的一部分，以确保其成功。 现在，我们完全致力于支持Span-2，以使其成功。