Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

PROJECT SUMMARY/ABSTRACT Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. There is an urgent need of therapeutic strategies that can provide safe and efficacious therapeutic effects to the hypoperfused brain with long-lasting endogenous neuroprotection for prevention of long-term neurologic dysfunction. Sufficient evidence has pointed out 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. Researchers at The University of Texas Health Science Center at Houston (UTSCH-H) have been able to incorporate Xe into liposomes and demonstrated that Xe-liposomal treatment post-stroke resulted in activation of endogenous brain protection following ischemic stroke. Corroborated mechanisms of Xe cytoprotection include the activation of endogenous cytoprotective molecules. In a NIH Phase I STTR, UTHSC-H collaborated with Zymo Research Corporation (Zymo), an experienced epigenetics company. We have shown proof of concept that intermittent Xenon(Xe)-liposomal treatment after stroke extends endogenous neuroprotection and induces epigenetic changes. Such sustained endogenous neuroprotection can be distinguished by a panel of differentially methylated biomarkers indicative of activation of specific signal transduction pathways. As brain pathological changes/progression post stroke last for months, to be clinically useful, to extend the window for neuroprotection duration. We hypothesize that endogenous neuroprotection seen via epigenetic markers can be enhanced and consolidated and into the chronic recovery phase, meanwhile, translate to clinical relevant model. We do this with a three-phase Xenon administration strategy. Two Xe formulations, Xe- liposomes and oral Xe formulation, will be used to extend the treatment window. We will establish maximal therapeutic efficacy and then translate into aged rat to increase rigor. The epigenetic biomarker panel identified in the Phase I STTR will be used to assess and validate Xe long term neuroprotective effects via the 3-phased administration regime in our Phase 2 STTR. Our goal is to optimize, validate, and translate the Xe liposomal formulation from phase I and evaluate a new complementary Xenon cyclodextrin (Xe-CD) formulation for oral administration for the chronic stroke recovery phase, whilst commercializing both Xe intravenous and oral formulations. We will continue epigenetic biomarker development as a diagnostic tool for evaluating stroke progression and treatment effects. Our aims are: 1) to develop final formulations of Xe-liposomes and Xe-enriched solution, and to evaluate parameters for product reproducibility and analysis pharmacokinetics of both formulations; 2) to maintain neuroprotection over a longer duration by adding an oral Xe-CD formulation following the IV acute Xe-liposomal agent administration (Acute to Chronic Recovery Strokes) in both adult and aged animals; and 3) to finalize, and scale the Xe-Liposomal and Xe-CD-Oral formulations for an IND application. Our long-term goal is to bring this strategy and these two formulations into clinical trials to stabilize and treat stroke from the acute to the long term recovery phase.PROJECT NARRATIVE Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. Neuroprotection for a long period post stroke could prevent or slow neurovascular deterioration. We aim to establish and translate two therapeutic agents (Xenon liposomes and Xe oral formulations) along with a novel delivery strategy to stimulate and consolidate long-term endogenous cytoprotection and tolerance to provide new opportunities for more complete stroke treatment. Identification of reliable biomarkers to guide determination of best frequency and duration of xenon-containing formulations and a translatable therapeutic administration protocol that allows consistent, long-lasting protection post stroke.