Identifying activators of interferon regulatory factors for neuroprotection

Abstract Stroke is a leading cause of morbidity and mortality in the United States However less than of patients are eligible for the current approved interventions of tissue plasminogen activator or thrombectomy We seek to develop new therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain an area of significant unmet medical need We have found that interferon regulatory factor IRF mediated gene transcription may represent an endogenous mechanism of neuroprotection that is associated with a reduction in ischemic injury Using both cell and mouse models of stroke we have demonstrated that administration of compounds following the ischemic insult that are known to induce IRF mediated gene transcription significantly reduces the extent of damage These results indicate that activation of IRF transcription factors following stroke may be a viable therapeutic intervention for the treatment of stroke patients The ultimate goal of this STTR program is to identify compounds that induce IRF transcription in both mouse and human cells but with minimal off target immune activity We will identify compounds with acceptable target specification optimize these compounds through hit to lead protocols and ultimately test for efficacy in a mouse model of cerebral ischemic injury We propose the following aims Aim Identify lead compounds for therapeutic development of an acute neuroprotectant using an experimentally validated high throughput screening platform Aim Evaluate and rank lead compounds through hit to lead characterization Aim Evaluate PK and tolerability of lead compounds and determine efficacy in a mouse model of cerebral ischemic injury Narrative Stroke is a leading cause of morbidity and mortality in the United States with approximately cases a year reported This proposal seeks to identify and validate small molecule activators of interferon regulatory factors as potential mediators of neuroprotection with the ultimate goal being the development of a stroke therapeutic