Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy In Stroke.

中风血管内血栓切除术后再灌注损伤的药物抑制。

基本信息

批准号：
10006866
负责人：
DAVID WARNER
金额：
$ 22.78万
依托单位：
BIOMIMETIX JV, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006866
关键词：
Abate Adverse effects Advocate Alteplase Apoptosis Apoptotic Arterial Fatty Streak BMX gene Basic Science Biological Assay Biological Markers Biology Brain Brain Injuries Catheters Cause of Death Clinical Clinical Sciences Clinical Trials Clinical Trials Design Cognitive Collaborations Consult Data Dose Female Filament Foundations Functional disorder Glioma Histologic Hour Human Inbred SHR Rats Infarction Inflammation Inflammatory Infusion procedures Intervention Intracarotid Intracarotid Infusion Ischemia Ischemic Penumbra Ischemic Stroke Italy Laboratories Laboratory Finding Laboratory Research Lead Legal patent Lesion MAPK phosphatase Maintenance Malignant Neoplasms Manganese Measures Mechanics Mediating Metabolic syndrome Metabolism Methods Middle Cerebral Artery Occlusion Modeling Monitor NF-kappa B Nervous System Physiology Neurologic Neurology Nitrogen Normal tissue morphology Outcome Outcome Measure Oxidation-Reduction Oxidative Stress Oxygen Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Pilot Projects Porphyrins Procedures Protocols documentation Radiation Protection Radiation therapy Rattus Recovery Reducing Agents Regulation Reperfusion Injury Reperfusion Therapy Safety Series Small Business Technology Transfer Research Standardization Stroke Symptoms Technology Therapeutic Therapeutic Index Thrombectomy Thromboembolism Thrombus Tissues Toxicology Transcriptional Activation Translating United States Universities Validation Wistar Rats Work aged base blood-brain barrier disruption brain tissue cohort comorbidity design disability drug development drug efficacy functional outcomes improved improved outcome in vitro activity in vivo male multidisciplinary neuroprotection nitrosative stress novel object recognition organ injury pre-clinical preclinical efficacy response response to brain injury restoration scale up screening stroke model stroke patient stroke therapy subcutaneous thrombolysis transcription factor treatment duration

项目摘要

Ischemic stroke is a leading cause of death and disability in the United States. This often is attributable to thrombus formation at an atherosclerotic plaque or thromboembolism. Patients who present within 4.5 hours of symptom onset are eligible for thrombolysis with tissue plasminogen activator (tPA). This serves <5% of victims. Recently, major advance has been made with proven efficacy from endovascular mechanical thrombectomy in combination with tPA. Despite this, <50% of treated patients have a good recovery. Basic and clinical science indicate that abrupt restoration of oxygen delivery to ischemic tissue causes reperfusion injury that amplifies/propagates adverse cascades initiated by the initial ischemic insult. There has been widespread call for pharmacologic intervention to mitigate reperfusion injury. The mechanistic basis for reperfusion injury is diverse, but fundamentally associated with rapid onset dysfunction of intracellular mechanisms responsible for regulation of oxygen metabolism. This leads to oxidative stress, inflammation, apoptosis, blood-brain barrier disruption and tissue damage. We are working closely with chemists who have synthesized manganese porphyrins (MnP). MnP have been highly characterized and serve as potent catalytic oxidoreductants. MnP have extraordinary efficacy to favorably modulate redox-mediated activation of transcription factors (e.g., NF-kB, Nrf2) and MAPK and phosphatases. MnP also serve as potent catalytic reductants of reactive oxygen/nitrogen species. We have repeatedly shown enduring improvement in experimental stroke long-term outcome after therapeutic MnP dosing. The lead MnP, BMX-001, now in human trials as a radioprotectant for normal tissue in the context of radiotherapy for brain malignancy, has achieved GMP synthesis, scale-up technology, and requisite preclinical toxicological screening. Based on highly encouraging pilot data, we propose BMX-001, given at endovascular thrombectomy reperfusion onset, as an adjunct pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, we will define optimal dosing and maximal ischemia duration before reperfusion and treatment onset that retains efficacy, measure long-term functional outcome in aged, metabolic syndrome, and spontaneously hypertensive rats, define interactions with tPA activity, and obtain independent laboratory efficacy validation. A Clinical Trial Consulting Team, consisting of independent stroke experts, will work in collaboration with Biomimetix to monitor go/no-go end-points and develop protocols for human dose-escalation trials.

缺血性中风是美国死亡和残疾的主要原因。这通常是归因于动脉粥样硬化斑块或血栓栓塞处的血栓形成。患者在症状发作的4.5小时内出现的人有资格与组织进行溶栓纤溶酶原激活剂（TPA）。这服务于<5％的受害者。最近，主要进步已经具有内血管内机械血栓切除术的疗效，结合 TPA。尽管如此，<50％的治疗患者康复良好。基础和临床科学表明突然恢复氧递送到缺血组织会导致再灌注损伤这会放大/传播受初始缺血性侮辱引发的不良级联反应。有广泛呼吁进行药物干预以减轻再灌注损伤。这再灌注损伤的机械基础是多种多样的，但从根本上与快速相关负责调节氧代谢的细胞内机制的发作功能障碍。这导致氧化应激，炎症，凋亡，血脑屏障破坏和组织损害。我们正在与具有合成锰卟啉合成的化学家紧密合作（MNP）。 MNP已被高度表征并用作有效的催化氧化剂。 MNP 具有特别调节氧化还原介导的转录激活的功效因素（例如NF-KB，NRF2）和MAPK和磷酸酶。 MNP也充当有效的催化活性氧/氮种的还原因子。我们反复显示持久治疗性MNP给药后实验中风长期结局的改善。领先 MNP，BMX-001，现在正在人类试验中作为正常组织的放射保护剂在用于大脑恶性肿瘤的放射疗法已达到GMP合成，扩大技术和必要的临床前毒理学筛查。基于极大鼓励的飞行员数据，我们建议 BMX-001，在血管内血栓切除术再灌注时给予，作为辅助优化血管内血栓切除术结果的药物。在第1阶段，我们将定义在再灌注和治疗发作之前，最佳剂量和最大缺血持续时间保留疗效，测量老年人，代谢综合征的长期功能结果，并自发性高血压大鼠，定义与TPA活性的相互作用，并获得独立实验室功效验证。由独立中风组成的临床试验咨询团队专家，将与BioMimetix合作监视GO/No-Go终点并开发人剂量降低试验的方案。