Scope: Supplement_Alpha5Beta1 Integrin inhibition as a Profound Blood-Brain Barrier Stabilizing Neuroprotective Stroke Therapy

Recent clinical trials such as MR CLEAN, ESCAPE, and EXTEND-IA have shown that endovascular thrombectomy is the new standard of care for large vessel occlusion to ensure recanalization of the vessel and reperfusion of the ischemic area. Incorporating intra-arterial (IA) administration of a potential neuroprotective agent following recanalization and reperfusion would be a simple adjunctive process, as the thrombectomy procedure provides arterial access to the cerebrovascular bed. However, while multiple neuroprotective agents have shown promise in animal studies, a lack of positive clinical data has limited their adoption in patient care. In this administrative supplement request to 5R01NS065842-09, we seek to capitalize on this idea using a novel experimental mouse stroke model that we have recently developed in our lab2 that allows us to administer neuroprotective agents via a selective IA route immediately after recanalization. Specifically, we plan to administer neuroprotective modulators of cerebrovascular activation, the peptide inhibitor of á5â1 integrin, ATN-161 (the experimental therapeutic agent in 5R01NS065842-09), and nitroglycerin. Importantly, both of these agents are FDA approved for intravascular administration for indications other than stroke, have well-characterized pharmacokinetics/pharmacodynamics, and are well tolerated. Thus, they may represent ideal stroke clinical trial therapeutic agents if they are successful in preclinical studies. Indeed, nitroglycerin already has some potential feasibility for human clinical stroke based on at least one trial in which it was administered systemically (intravenous)3. Furthermore, because these agents work on different aspects of cerebrovascular function (ATN-161 stabilizes the blood-brain barrier and nitroglycerin promotes vasodilation), we hypothesize that they could have synergistic therapeutic effect if co-administered.