Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

PROJECT SUMMARY ABSTRACT Stroke injury is a process that occurs over a long duration with pathologic changes that result in long term neurologic dysfunction For stroke there exists an important need for a strategy that can provide safe and efficacious stabilization to the hypoperfused brain and initialize long lasting endogenous neuroprotection for prevention of long term neurologic dysfunction Sufficient evidence has shown that xenon Xe a bioactive gas has profound neuroprotective effects with advantages of rapid diffusion across the blood brain barrier BBB with minimal side effects In recent novel studies researchers at The University of Texas Health Science Center at Houston UTHealth incorporated Xe into liposomes and demonstrated that Xe liposome treatment post stroke resulted in activation of endogenous brain protection following ischemic stroke and subarachnoid hemorrhage Corroborated mechanisms of Xe cytoprotection include the activation of endogenous cytoprotective molecules Repetitive administration of Xe liposomes extends the protective effects over time Although the detailed mechanisms underlying repetitive administration induced long term protection remain unclear emerging evidence supports that such adaptive phenotypes are epigenetically mediated As epigenetic post conditioning is highly related to the potency frequency and duration of stimuli we hypothesize that repetitive intermittent Xe liposomal administration at an optimal frequency and duration can induce epigenetic post conditioning resulting in long term effects This hypothesis leads to the collaboration between Zymo Research Corporation Zymo an experienced epigenetics company and UTHealth UTHealth holds the patents containing the claims for the use of Xe containing liposomes for prevention and treatment of stroke From a commercialization standpoint Xe liposome is an attractive therapeutic candidate due to its low side effects and markedly high BBB diffusion The goals of this proposal are to optimize the Xe liposomal administration protocol for long term cytoprotection and to find the best epigenetic markers that directly correlate Xe treatment to long term cytoprotective effects in stroke treatment Our aims are to determine the optimal frequency and duration of Xe liposomal administration and demonstrate sustained cytoprotection by repetitive Xe liposomal administrations for ischemic stroke treatment and to determine epigenetic signatures to indicate Xe sustained cytoprotection Our long term goals STTR Phase II and beyond are to develop an optimal Xe liposomal delivery strategy using essential epigenetic markers to demonstrate acute and long term neuroprotection following stroke and to translate this technology into a clinical product with sustained stroke stabilization effects PROJECT NARRATIVE Stroke injury occurs over a long duration through pathologic changes leading to long term neurologic dysfunction Neuroprotection targeted to the long term effect could prevent or slow neurovascular deterioration in progressive ischemic stroke We aim to establish a novel therapeutic delivery strategy to stimulate long term endogenous cytoprotection and tolerance to provide valuable opportunities for stroke treatment Identification of reliable biomarkers to guide determination of best frequency and duration of xenon containing liposome delivery will provide an efficacious and translatable therapeutic administration protocol that allows consistent long lasting protection in diverse types of patients