Mitoquinone/mitoquinol mesylate as oral and safe Postexposure Prophylaxis for Covid-19

米托醌/甲磺酸米托喹诺作为 Covid-19 的口服且安全的暴露后预防

• 批准号: 10727092
• 负责人: Theodoros Kelesidis
• 金额: $ 24.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727092
• 关键词: 2019-nCoV; Accounting; Address; Adult; Adverse effects; Aging; Agonist; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Antiviral Agents; Antiviral Therapy; Apoptosis; Apoptotic; Attenuated; Binding; Bioinformatics; COVID-19; COVID-19 morbidity; COVID-19 treatment; Cancer Patient; Cell Death; Cell physiology; Clinical; Clinical Trials; Control Groups; Coronavirus; Data; Development; Double-Blind Method; Energy-Generating Resources; Ensure; Epithelial Cells; Exhibits; Exposure to; FDA approved; Foundations; Funding Opportunities; Generations; Goals; Hour; Human; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Liver Dysfunction; Long COVID; Lung; Mediating; Mesylates; Mitochondria; Monitor; Morbidity - disease rate; Mus; Nucleosides; Oral; Outpatients; Participant; Pathogenesis; Pathway interactions; Paxlovid; Persons; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Property; Prophylactic treatment; Protease Inhibitor; Public Health; RNA Viruses; Randomized; Reactive Oxygen Species; Research Design; Resistance; Ritonavir; SARS coronavirus; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 variant; Safety; Sample Size; Severe Acute Respiratory Syndrome; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Vaccinee; Vascular Diseases; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; airway epithelium; anti-viral efficacy; attenuation; clinically relevant; comorbidity; design; dietary supplements; efficacy evaluation; efficacy outcomes; efficacy study; follow-up; high risk; high risk population; in vivo; innovation; lung injury; mitoquinone; nirmatrelvir; novel; novel therapeutics; nucleoside analog; open label; phase 2 study; post SARS-CoV-2 infection; pre-exposure prophylaxis; prevent; primary outcome; recruit; safety outcomes; severe COVID-19; therapeutic target; tissue injury; treatment group; variants of concern

PROJECT SUMMARY/ABSTRACT Current oral antivirals used against SARS-CoV-2 infection such as protease inhibitors have limitations such as absence of anti-inflammatory effects and rebound COVID-19 after a 5-day course of outpatient antiviral treatment. Novel antiviral therapies against SARS-CoV-2 are urgently needed that ideally also limit inflammatory responses that contribute to morbidity from COVID-19. Reactive oxygen species (ROS) impair cellular functions and drive pro-inflammatory signaling and pathogenesis of infections with RNA viruses like coronavirus. Mitochondria are the main source of energy and ROS (mito-ROS). Mito-ROS are regulated by the antioxidant Nrf2 pathway that mediates pathogenesis and tissue damage of viral infections. We showed that MitoQ, a mitochondrial antioxidant and Nrf2 agonist, inhibits in vitro and in vivo viral replication of several SARS-CoV-2 variants of concern (VOC) and associated inflammatory response and apoptosis in airway epithelial cells through the Nrf2 pathway. Given that MitoQ is a diet supplement that is safe and immediately available to humans for use as possible therapeutic, we also showed antiviral efficacy of MitoQ in humans in a carefully designed open label clinical trial of post exposure prophylaxis (PEP) of MitoQ, compared to no MitoQ (control group), to prevent development of SARS-CoV-2 infection after high-risk exposure to a person with confirmed SARS-CoV-2 infection. MitoQ was well tolerated. We hypothesize that MitoQ attenuates the SARS- CoV-2-induced aberrant mito-ROS and Nrf2 pathway in epithelial cells and ultimately tissue injury that drives development and progression of severe COVID-19. The goal of this application is to determine if MitoQ can be used as novel oral safe outpatient post-exposure prophylaxis treatment against development of severe COVID-19. We propose the first proof-of concept randomized, double-blind, placebo-controlled Phase II efficacy study (RCT) with oral MitoQ use in adults at high risk for development of COVID-19, to further establish the safety and the efficacy of MitoQ against development of SARS-CoV-2 infection. We will include 2 treatment groups (MitoQ 20 mg daily, placebo) and we aim to recruit a total of 112 participants in total (50 per group accounting for 10% attrition). The primary outcome of efficacy will be the development of SARS- CoV-2 infection after high-risk exposure. The primary outcome of safety will be the proportion of participants exhibiting adverse effects of any grade. Given that attenuation of detrimental host responses that propagate viral replication may impose a higher barrier to generation of resistant viruses, this study will directly test MitoQ as a novel oral, safe, potent therapeutic strategy for COVID-19 against emerging SARS-CoV-2 VOCs. Our proposal will set the foundation of larger clinical trial that will advance use of MitoQ for COVID-19 to supplement existing treatments.

项目总结/摘要 目前用于SARS-CoV-2感染的口服抗病毒药物如蛋白酶抑制剂具有局限性， 门诊抗病毒治疗5天疗程后无抗炎作用，COVID-19反弹 治疗目前迫切需要针对SARS-CoV-2的新型抗病毒疗法， 导致COVID-19发病的炎症反应。活性氧（ROS）损害 细胞功能和驱动促炎信号和RNA病毒感染的发病机制， 冠状病毒。线粒体是机体能量和活性氧的主要来源。线粒体活性氧是由 抗氧化剂Nrf 2途径，介导病毒感染的发病机制和组织损伤。我们发现 MitoQ是一种线粒体抗氧化剂和Nrf 2激动剂，可抑制几种病毒的体外和体内病毒复制。 SARS-CoV-2相关变异体（VOC）与气道炎症反应和细胞凋亡 上皮细胞通过Nrf 2途径。鉴于MitoQ是一种安全的饮食补充剂， 作为可能的治疗方法，我们还在一个研究中显示了MitoQ在人类中的抗病毒功效。 与无MitoQ相比，MitoQ暴露后预防（PEP）的精心设计的开放标签临床试验 （对照组），以防止在接触高危人群后发生SARS-CoV-2感染， 证实感染了SARS-CoV-2。MitoQ耐受性良好。我们假设MitoQ能减弱SARS病毒- CoV-2在上皮细胞中诱导异常的线粒体-ROS和Nrf 2通路，并最终导致组织损伤， 严重COVID-19的发展和进展。本应用程序的目标是确定MitoQ是否可以 用作新型口服安全的门诊暴露后预防治疗， 2019冠状病毒病。我们提出了第一个概念验证随机，双盲，安慰剂对照的第二阶段， 在患有COVID-19高风险的成人中进行口服MitoQ的有效性研究（RCT），以进一步 确定MitoQ对SARS-CoV-2感染发展的安全性和有效性。我们将包括 2个治疗组（MitoQ每日20 mg，安慰剂），我们的目标是招募总计112名参与者（50 每组占10%的损耗）。疗效的主要结果将是SARS的发展- 高风险暴露后的CoV-2感染。安全性的主要结局将是参与者的比例 表现出任何级别的不良反应。鉴于有害的宿主反应的衰减， 病毒复制可能会对耐药病毒的产生施加更高的屏障，本研究将直接检测MitoQ 作为一种新型的口服、安全、有效的COVID-19治疗策略，对抗新出现的SARS-CoV-2 VOCs。我们 该提案将为更大规模的临床试验奠定基础，该试验将推动MitoQ在COVID-19中的使用， 补充现有的治疗方法。