Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

项目总结/摘要 中风损伤发生在一个长期的病理变化，导致长期的神经系统损伤， 功能障碍迫切需要能够提供安全有效的治疗方法的治疗策略。 对低灌注脑的长期内源性神经保护作用， 神经功能障碍有充分的证据表明，氙（Xe）作为一种生物活性气体， 神经保护作用，具有快速扩散穿过血脑屏障（BBB）的优点， 方面的影响.德克萨斯大学休斯顿健康科学中心（UTSCH-H）的研究人员已经能够 将Xe掺入脂质体中，并证明中风后Xe-脂质体治疗导致激活 缺血性中风后内源性脑保护的作用。经证实的抗肿瘤细胞保护机制 包括内源性细胞保护分子的激活。在NIH I期STTR中，UTHSC-H与 Zymo Research Corporation（Zymo）是一家经验丰富的表观遗传学公司。我们已经证明了 中风后间歇性氙（氙）-脂质体治疗延长内源性神经保护的概念， 诱导表观遗传变化。这种持续的内源性神经保护作用可以通过一组 差异甲基化的生物标志物指示特定信号转导途径的活化。如脑 卒中后病理变化/进展持续数月，在临床上有用， 神经保护持续时间。我们假设，通过表观遗传标记观察到的内源性神经保护作用可能是 增强和巩固并进入慢性恢复期，同时转化为临床相关模型。 我们采用三阶段氙气管理策略来实现这一点。两种药物制剂，脂质体和口服药物 制剂，将用于延长治疗窗口。我们将建立最大的治疗效果， 然后转化成老年大鼠来增加僵硬度在I期STTR中确定的表观遗传生物标志物组将 用于评估和验证通过3阶段给药方案的长期神经保护作用， 我们的第二阶段STTR。我们的目标是优化，验证，并从第一阶段翻译的脂质体制剂 并评估一种新的补充氙环糊精（Xe-CD）制剂，用于口服给药， 慢性中风恢复期，同时将静脉注射和口服制剂商业化。我们将 继续开发表观遗传生物标志物，作为评估卒中进展和治疗的诊断工具 方面的影响. 我们的目标是：1）开发Xe-脂质体和Xe富集溶液的最终制剂， 用于两种制剂的产品再现性和分析药代动力学的参数; 2）维持 通过在IV急性Xe-脂质体给药后加入口服Xe-CD制剂， 在成年和老年动物中的药剂施用（急性至慢性恢复性中风）;以及3）完成，以及 扩大Xe-Liposomal和Xe-CD-Oral制剂的IND申请规模。 我们的长期目标是将这一策略和这两种制剂带入临床试验，以稳定和治疗 中风从急性期到长期恢复期。

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.