Stroke Preclicinal Assessment Network

关于潜在卒中疗法的探索性动物数据并不能预测临床成功。那里 关注的是临床前研究的设计和进行，它们的重复性和普适性。这个 对这一挑战的回应是NINDS卒中前临床评估网络(SPAN)，一个不偏不倚的 翻译性卒中研究中临床前验证性研究的多中心平台。MGH团队是 在同行审查为SPAN(SPAN-1)第一次迭代选择的六个实验室中。 我们为SPAN-1的设计做出了重大贡献。MGH负责磁共振成像方案 SPAN-1，并帮助开发了一条全自动分析管道。然后我们捐献了近400只动物 在两年内测试六种不同的急性中风干预措施。每只动物都接受了两次核磁共振检查(第2天和第30天) 以及两项神经学测试(第7天和第28天)。在28天的存活期内，总死亡率仅为10%。我们的 技术损失仅为17头动物。只有3个协议偏离或违规。我们的 总体目标是在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团队使用各种局灶性大脑组织共同发表了100多篇手稿 啮齿类动物的缺血模型和急性和慢性神经结局读数。MGH还将带来 SPAN-2的其他创新方法，例如引入出血的MRI读数 变形、血脑屏障(BBB)破坏和气管造影术。我们将与后者相辅相成 在随访期结束时进行静息状态功能连接(RSFC)的光学成像。 目标1.为SPAN-2作为测试实验室做出贡献。我们发誓要在SPAN-1重复我们的成功， 作为团队与网络的其余部分合作，并通过内置冗余来维持我们的高标准 确保我们在面对人员变动和流行病和天气等破坏性事件时的应变能力。 目的2.引入创新的新结构和功能指标，以丰富跨度读数。我们会 超越招募受试者的范围，引入创新的读数，如出血、水肿、 结构和功能连通性以及组织学分析，这些都不是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性疗效和安全性数据。我们假设跨度将会有 统计能力和不偏不倚的结构，以提供确凿的证据来证实或驳斥已发表的 缺血性卒中合并再灌流前瞻性脑保护治疗的研究数据。 十多年来，我们一直倡导并热情支持公正的 多中心临床前试验平台。我们热情地作为SPAN-1的一部分进行工作，以确保它的成功。 现在，我们完全致力于支持SPAN-2，使其也取得成功。

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.