DRα MOG A Novel Immunomodulatory Therapeutic for Stroke

This is a Phase I STTR to investigate the preclinical efficacy of a novel immunomodulator DR MOG in a clinically relevant thromboembolic stroke model in mice We have previously shown that T cells are activated after stroke infiltrate brain and exacerbate ischemic brain damage Strategies that reduce T cell activation and brain tissue infiltration have been investigated as potential therapeutic strategies for stroke however non specific inhibition of T cell function is immunosuppressive We therefore developed Recombinant T cell receptor TCR Ligands RTLs which are partial MHC II molecules comprised of covalently linked and chains tethered to antigenic peptides Early RTL constructs were successful in protecting against ischemia induced brain injury but only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient A significant limitation for using these early RTL constructs to treat human stroke is the need to rapidly match recipient MHC class II with the domain of the pMHC construct We therefore designed a novel recombinant protein comprised of the HLA DR domain linked to MOG peptide DR MOG but lacking the domain found in pMHC Because the DR domain is present in all humans and would not be recognized as foreign treatment using DR constructs would not require HLA screening of potential recipients In a proof of principle study we demonstrated that four daily treatments with DR MOG significantly reduced infarct size after stroke in mice That study however was conducted using the intraluminal middle cerebral artery occlusion MCAO model which causes mechanical rather than thromboembolic occlusion the most common cause of human stroke To more faithfully mimic clinical stroke we have developed a novel thromboembolic model of stroke in mouse which will form the basis of the current proposal Furthermore aging and biological sex are well documented key determinants of stroke outcome in part by exerting differential influences on stroke induced inflammatory response The proposed STTR will further characterize the protective effect of DR MOG using the clinically relevant thromboembolic model of stroke and the clinically important variables of time of initial treatment sex and age to estimate how broadly DR MOG could be used to treat stroke patients Stroke causes inflammation in brain which makes stroke worse The inflammatory cells responsible for brain inflammation after stroke include a cell type called T cells Inhibiting T cells indiscriminately causes reduced immunity and infections We have developed a novel therapeutic agent which causes selective inhibition of some of T cell functions which leads to reduced inflammation after stroke selectively without affecting overall immunity We will use a novel model of stroke which mimics human stroke to show that this drug reduces brain damage and improves functions after stroke in both young and old males and females