An antioxidant enzyme to suppress hyperinflammation induced by SARS-CoV-2

一种抑制 SARS-CoV-2 引起的过度炎症的抗氧化酶

• 批准号: 10665424
• 负责人: Jing Wen
• 金额: $ 38.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665424
• 关键词: 2019-nCoV; Age; Air; Alveolar Cell; Antibodies; Antibody Therapy; Biodistribution; Biomedical Engineering; Blood - brain barrier anatomy; Blood Circulation; Brain; COVID-19; COVID-19 pandemic; COVID-19 pathogenesis; COVID-19 patient; COVID-19 therapeutics; COVID-19 treatment; Cell membrane; Cessation of life; Chemicals; Chronic Disease; Collaborations; Communicable Diseases; Diabetes Mellitus; Diffuse; Disease; Disease Outbreaks; Drug Kinetics; Effectiveness; Enzyme Stability; Enzymes; Epithelial Cells; Erythrocytes; Foundations; Future; Goals; Growth Factor; Half-Life; Homeostasis; Human; Hydrogen Peroxide; Immune; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Influenza; International; Intravenous Immunoglobulins; Janus kinase; Laboratories; Leukocytes; Liquid substance; Liver; Macaca mulatta; Molecular; Molecular Target; Monoclonal Antibodies; Morbid Obesity; Mus; Natural Immunity; Nature; Neoplasm Metastasis; Neuraxis; Organ; Oxidative Stress; Oxygen; Patients; Peptide Hydrolases; Persons; Plasma; Pneumonia; Production; Proteins; Protocols documentation; Public Health; Publishing; Pulmonology; Reactive Oxygen Species; Repression; Research; Research Personnel; Respiratory Disease; Respiratory Tract Infections; Respiratory syncytial virus; Risk Factors; Role; SARS-CoV-2 infection; Smoking; Steroids; System; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Time; Tissues; Toxic effect; Treatment Efficacy; Viral; Virus Diseases; Virus Replication; Water; Work; alveolar epithelium; anakinra; antioxidant enzyme; base; career; catalase; catalyst; cell behavior; cytokine; immunogenicity; immunoregulation; improved; mortality; mouse model; multidisciplinary; nanocapsule; nanoencapsulated; oxidative damage; pandemic disease; patient subsets; prevent; severe COVID-19; success; therapeutic enzyme; therapeutic protein; therapeutically effective; tocilizumab; treatment strategy; virology

PROJECT SUMMARY The COVID-19 pandemic has taken a significant toll on people worldwide, and current treatment is mainly supportive. While the pathogenesis of COVID-19 remains elusive, accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have virally driven hyperinflammation and immune dysregulation. We propose herein reactive oxygen species contribute to hyperinflammation and immune dysregulation in severe COVID-19 patients, which can be treated by an antioxidant enzyme—catalase that regulates cytokine production, protects against oxidative injury, and represses replication of SARS-CoV-2. This therapeutic based on catalase, the most abundant antioxidant enzyme ubiquitously present in the liver, erythrocytes and alveolar epithelial cells, is the most effective catalyst to breakdown hydrogen peroxide and minimize the downstream reactive oxygen species. The potential of catalase as a therapeutic agent has been explored for different diseases in vitro and in mouse models, including influenza-associated pneumonia, respiratory infections caused by respiratory syncytial virus (RSV), and inflammatory disease associated with oxidative stress. However, the efficacy of catalase has been hampered by its poor stability and short plasma half-life. Particularly, in the context of COVID-19 patients, death of the alveolar cells and inflammation could result in high local concentrations of proteases, further deteriorating the stability of catalase. We recently published an effective delivery system of catalase using the nanocapsule technology. Catalase delivered by nanocapsules assists to regulate production of cytokines and protect oxidative injury, as demonstrated in human leukocytes and alveolar epithelial cells, and repress replication of SARS-CoV-2 in rhesus macaques, without noticeable toxicity. In this proposal, we will further investigate the immunoregulatory effect of catalase nanocapsules on hyperinflammation induced by SARS-CoV-2 ex vivo, further optimize their biodistribution, pharmacokinetics, and delivery efficiency to SARS-CoV-2 infected organs, and test their therapeutic efficacy in the SARS-CoV-2 infection mice developing respiratory disease resembling severe COVID-19. Success of this project may provide an effective therapeutic solution for the pandemic, as well as treatment of hyperinflammation induced by virus infection in general.

项目总结 新冠肺炎疫情已经给全球人民造成了重大损失，目前的治疗主要是 支持我。虽然新冠肺炎的发病机制仍不清楚，但越来越多的证据表明， 重症新冠肺炎患者亚群可能存在病毒驱动的炎症和免疫亢进 监管失调。我们认为，在这里，活性氧参与了过度炎症和免疫。 严重新冠肺炎患者的调节失调，可以通过一种抗氧化酶-过氧化氢酶来治疗 调节细胞因子的产生，防止氧化损伤，并抑制SARS-CoV-2的复制。这 基于过氧化氢酶的治疗作用，过氧化氢酶是肝脏中普遍存在的最丰富的抗氧化酶， 红细胞和肺泡上皮细胞，是分解过氧化氢和 最大限度地减少下游的活性氧。过氧化氢酶作为治疗剂的潜力已经被 在体外和小鼠模型中探索不同的疾病，包括流感相关性肺炎， 由呼吸道合胞病毒(RSV)引起的呼吸道感染，以及与 氧化应激。然而，过氧化氢酶的稳定性差，血浆时间短，其药效一直受到阻碍。 半衰期。尤其是在新冠肺炎患者中，肺泡细胞死亡和炎症可能 导致局部蛋白酶浓度较高，进一步恶化了过氧化氢酶的稳定性。我们最近 利用纳米胶囊技术发布了一种有效的过氧化氢酶给药系统。过氧化氢酶递送人 纳米胶囊有助于调节细胞因子的产生并保护氧化损伤，如 人白细胞和肺泡上皮细胞，并抑制SARS-CoV-2在猕猴体内的复制， 没有明显的毒性。在这项建议中，我们将进一步研究过氧化氢酶的免疫调节作用 纳米胶囊对SARS-CoV-2诱导的体外炎症反应的影响，进一步优化其生物分布， SARS-CoV-2感染器官的药代动力学和给药效率，并测试其治疗效果 感染SARS-CoV-2的小鼠出现类似严重新冠肺炎的呼吸道疾病。这件事成功了 该项目可能为这一大流行提供有效的治疗解决方案，以及治疗 一般由病毒感染引起的高度炎症。