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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

基本信息

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
项目类别：
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

项目摘要

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