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 Rho associated 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.
Ischemic stroke is among the most common causes of death and disability, with significant long-term economic burden and loss of quality of life. Numerous therapeutic interventions that have been efficacious in the laboratory have failed to show efficacy in clinical trials, including pharmacological neuroprotection. New therapeutic approaches are needed, and ROCK inhibition appears to hold considerable promise.
|Rost, Natalia S; Cougo, Pedro; Lorenzano, Svetlana et al. (2018) Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J Cereb Blood Flow Metab 38:75-86|
|Lorenzano, Svetlana; Rost, Natalia S; Furie, Karen L (2018) Response by Lorenzano et al to Letter Regarding Article, ""Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke"". Stroke 49:e264|
|Matsouaka, Roland A; Singhal, Aneesh B; Betensky, Rebecca A (2018) An optimal Wilcoxon-Mann-Whitney test of mortality and a continuous outcome. Stat Methods Med Res 27:2384-2400|
|Lorenzano, Svetlana; Rost, Natalia S; Khan, Muhib et al. (2018) Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke. Stroke 49:630-637|
|Murphy, Meredith P; Kuramatsu, Joji B; Leasure, Audrey et al. (2018) Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage. Stroke 49:2652-2658|
|Schwamm, Lee H; Wu, Ona; Song, Shlee S et al. (2018) Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol 83:980-993|
|Atem, Folefac D; Qian, Jing; Maye, Jacqueline E et al. (2017) Linear Regression with a Randomly Censored Covariate: Application to an Alzheimer's Study. J R Stat Soc Ser C Appl Stat 66:313-328|
|Dumitrascu, Oana M; Torbati, Sam; Tighiouart, Mourad et al. (2017) Pitfalls and Rewards for Implementing Ocular Motor Testing in Acute Vestibular Syndrome: A Pilot Project. Neurologist 22:44-47|
|Marini, Sandro; Morotti, Andrea; Ayres, Alison M et al. (2017) Sex differences in intracerebral hemorrhage expansion and mortality. J Neurol Sci 379:112-116|
|Etherton, Mark R; Wu, Ona; Cougo, Pedro et al. (2017) Structural Integrity of Normal Appearing White Matter and Sex-Specific Outcomes After Acute Ischemic Stroke. Stroke 48:3387-3389|
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