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.
|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|
|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|
|(2017) 19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium. Neurol Genet 3:S2-S11|
|Lima, Fabricio O; Silva, Gisele S; Furie, Karen L et al. (2016) Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 47:1997-2002|
|Atem, Folefac D; Qian, Jing; Maye, Jacqueline E et al. (2016) Multiple Imputation of a Randomly Censored Covariate Improves Logistic Regression Analysis. J Appl Stat 43:2886-2896|
|Anderson, Christopher D; Falcone, Guido J; Phuah, Chia-Ling et al. (2016) Genetic variants in CETP increase risk of intracerebral hemorrhage. Ann Neurol 80:730-740|
|Gesierich, Benno; Opherk, Christian; Rosand, Jonathan et al. (2016) APOE ?2 is associated with white matter hyperintensity volume in CADASIL. J Cereb Blood Flow Metab 36:199-203|
|Reijmer, Yael D; van Veluw, Susanne J; Greenberg, Steven M (2016) Ischemic brain injury in cerebral amyloid angiopathy. J Cereb Blood Flow Metab 36:40-54|
|Hirai, Kelsi K; Groisser, Benjamin N; Copen, William A et al. (2016) Comparing prognostic strength of acute corticospinal tract injury measured by a new diffusion tensor imaging based template approach versus common approaches. J Neurosci Methods 257:204-13|
Showing the most recent 10 out of 123 publications