Arise

溶栓的安全治疗窗狭窄，限制了其在大多数急性卒中患者中的应用。 需要更广泛的具有增强的安全性和有效性的再灌注策略。Rhoassociated抑制 蛋白激酶（ROCK）是一种这样的治疗干预。ROCK抑制剂改善脑血 脑血流（CBF），并已在各种实验性中风模型中证明了疗效。在这 在获得拨款申请后，我们建议采取第一个翻译步骤，对岩石进行全面的临床试验 作为缺血性中风的治疗靶点。我们鉴定了一种新的化合物（SLx-2119; Surface Logix，Boston， MA），其对ROCK 2的选择性比ROCK 1和其他蛋白激酶高100倍，并且似乎具有 更有利的安全性。该化合物目前正在健康志愿者中进行安全性测试。我们 提出了一项为期4年的转化研究，旨在确认使用SLx选择性抑制ROCK 2的疗效， 2119在临床前模型（第1-2年）中，并在30例人类卒中患者中进行了首次剂量递增毒性研究 患者（3-4年）。目的1：检测SLx-2119在实验性脑卒中中的安全性和有效性。基础上 初步数据显示在标准大脑中动脉闭塞模型中的有效性，我们建议进行 临床前研究对于SLx-2119从实验室转化为人类卒中至关重要。目标2：测试 在急性缺血性卒中患者中使用SLx-2119抑制R 0 CK 2的安全性。我们计划进行IB阶段 在症状发作后12小时内接受递增剂量治疗的缺血性卒中患者中进行的剂量探索研究 SLx-2119主要目的是通过确定最大耐受剂量来评价SLx-2119的安全性 （MTD）。此外，我们将评估SLx-2119的药代动力学，测量ROCK活性，并获得 额外的人类中风安全性数据。

The narrow therapeutic window of safety for thrombolysis limits its use in the majority of acute stroke patients. A broader range of reperfusion strategies with enhanced safety and efficacy profiles is needed. Inhibition of Rhoassociated protein kinase (ROCK) is one such therapeutic intervention. ROCK inhibitors improve cerebral blood flow (CBF) in ischemic brain, and have demonstrated efficacy in a variety of experimental stroke models. In this grant application, we propose to take the first translational step toward comprehensive clinical testing of ROCK as a therapeutic target in ischemic stroke. We identified a novel compound (SLx-2119; Surface Logix, Boston, MA) that is 100-fold more selective towards ROCK2 than ROCK1 and other protein kinases, and appears to have a more favorable safety profile. This compound is currently undergoing safety testing in healthy volunteers. We propose a 4-year translational study designed to confirm the efficacy of selective ROCK2 inhibition using SLx- 2119 in pre-clinical models (Years 1-2) and perform the first dose escalation toxicity study in 30 human stroke patients (Years 3-4). Aim 1: Test the safety and efficacy of SLx-2119 in experimental stroke. Building on preliminary data showing efficacy in a standard middle cerebral artery occlusion model, we propose to perform preclinical studies that are critical for translation of SLx-2119 from bench to human stroke. Aim 2: Test the safety of R0CK2 inhibition using SLx-2119 in acute ischemic stroke patients. We plan to conduct a Phase IB dose-finding study in ischemic stroke patients treated within 12 hours of symptom onset at escalating doses of SLx-2119. The primary aim is to evaluate the safety of SLx-2119, by identifying the maximum tolerated dose (MTD). In addition, we will assess the pharmacokinetics of SLx-2119, measure ROCK activity, and obtain additional human stroke safety data.