Arise

溶栓治疗的安全治疗窗口狭窄，限制了其在大多数急性中风患者中的应用。 需要更广泛的再灌注策略，增强安全性和有效性。对RhoAssociation的抑制 蛋白激酶(ROCK)就是这样一种治疗干预措施。岩石抑制剂改善脑血 该药可改善脑缺血时的血流(CBF)，并已在多种实验性中风模型中显示出疗效。在这 批准申请，我们建议向全面的ROCK临床测试迈出第一步 作为治疗缺血性卒中的靶点。我们鉴定了一种新的化合物(SLX-2119；Surface Logix，波士顿， Ma)，它对ROCK2的选择性是ROCK1和其他蛋白激酶的100倍，而且似乎 更有利的安全状况。这种化合物目前正在健康志愿者身上进行安全性测试。我们 提出一项为期4年的翻译研究，旨在证实使用SLX-2选择性抑制ROCK2的疗效 2119在临床前模型中(1-2年)，并在30例人类中风患者中进行首剂递增毒性研究 患者(3-4岁)。目的1：检测SLX-2119治疗实验性卒中的安全性和有效性。在基础上建设 在标准的大脑中动脉闭塞模型中显示有效性的初步数据，我们建议进行 临床前研究对于SLX-2119从板凳到人类卒中的转化至关重要。目标2：测试 急性缺血性卒中患者应用SLX-2119抑制R0CK2的安全性。我们计划进行IB阶段 缺血性卒中患者发病后12小时内递增剂量的剂量发现研究 SLX-2119。主要目的是通过确定最大耐受量来评估SLX-2119的安全性 (MTD)。此外，我们将评估SLX-2119的药代动力学，测量岩石活性，并获得 额外的人类中风安全数据。

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.