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.

项目摘要 COVID-19大流行对全球人的造成了重大损失，目前的治疗主要是 支持。虽然Covid-19的发病机理仍然难以捉摸，但积累的证据表明A 严重COVID-19患者的亚组可能实际上具有驱动的超炎和免疫力 失调。我们在此提出的活性氧有助于过度炎症和免疫 严重的COVID-19患者的失调，可以通过抗氧化剂酶（可催化酶）进行治疗。 调节细胞因子的产生，预防氧化损伤并抑制SARS-COV-2的复制。这 基于过氧化氢酶的治疗性，最丰富的抗氧化剂酶普遍存在肝脏中， 红细胞和肺泡上皮细胞是分解过氧化氢和的最有效催化剂 最小化下游活性氧。过氧化氢酶作为治疗剂的潜力已经 探索了体外和小鼠模型中不同疾病的探索，包括与影响ZA相关的肺炎， 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，过氧化氢酶的效率受到其稳定性较差和短血浆的阻碍 半衰期。特别是，在199名患者的背景下，肺泡细胞的死亡和炎症可能 导致高局部蛋白酶浓度，进一步恶化过氧化氢酶的稳定性。我们最近 使用纳米胶囊技术发布了有效的过氧化氢酶交付系统。过氧化氢酶由 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，并抑制恒河猕猴中SARS-COV-2的复制 没有明显的毒性。在此提案中，我们将进一步研究过氧化氢酶的免疫调节作用 SARS-COV-2离体诱导的高炎症上的纳米胶囊，进一步优化了其生物分布， 药代动力学和对SARS-COV-2感染器官的递送效率，并测试其治疗效率 SARS-COV-2感染小鼠患有类似于严重Covid-19的呼吸道疾病。成功的成功 项目可以为大流行提供有效的治疗解决方案，并治疗 通常，病毒感染引起的高炎症。