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Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

表观遗传标记和持续细胞保护用于中风治疗

基本信息

批准号：
10322190
负责人：
Keith Booher
金额：
$ 84.14万
依托单位：
ZYMO RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322190
关键词：
Acute Adult Aftercare Animals Biodistribution Biological Markers Blood - brain barrier anatomy Blood specimen Brain Chronic Clinical Clinical Trials Cyclodextrins Cytoprotection Deterioration Development Diagnostic Diffusion Dose Drug Kinetics Ensure Epigenetic Process Ethanol Formulation Freeze Drying Frequencies Gases Goals Health Sciences Human Injections Injury Intravenous Ischemic Stroke Laboratories Liposomes Long-Term Effects Maintenance Methods Methylation Modeling Motor Neurologic Neurologic Dysfunctions Oral Oral Administration Pathologic Pharmacologic Substance Phase Powder dose form Preparation Prevention Procedures Protocols documentation Quality Control Rattus Reaction Recovery Recovery of Function Reproducibility Research Research Personnel Safety Signal Transduction Pathway Small Business Technology Transfer Research Stroke Testing Texas Therapeutic Therapeutic Agents Therapeutic Effect Translating Treatment Efficacy Treatment Protocols United States National Institutes of Health Universities Xenon acute stroke aged biomarker development biomarker panel chronic stroke clinically relevant cognitive testing diagnostic tool epigenetic marker epigenetic regulation experience improved mature animal neuroprotection neurovascular novel novel therapeutics operation post stroke prevent side effect stroke recovery stroke therapy tool treatment effect young adult

项目摘要

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.

项目总结/文摘

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Liposome-Based Carriers for CRISPR Genome Editing.

DOI：
10.3390/ijms241612844
发表时间：
2023-08-16
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Yin, Xing;Harmancey, Romain;McPherson, David D.;Kim, Hyunggun;Huang, Shao-Ling
通讯作者：
Huang, Shao-Ling

Co-Delivery of Therapeutics and Bioactive Gas Using a Novel Liposomal Platform for Enhanced Treatment of Acute Arterial Injury.