Targeting DNA Damage Repair Pathways to Reduce SARS-CoV-2 Replication in the Airways
Abstract
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus, severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). COVID-19 is currently causing a pandemic and endangering lives globally. As of June 7, 2020, the disease has spread to over 212 countries or territories, and the number of COVID-19 cases has surpassed 7,100,000 globally, with over 408,000 deaths. In the United States, there have been over 1,900,000 cases and over 111,000 deaths. The major causes of morbidity and mortality from COVID-19 are severe acute lung injury with diffuse alveolar damage resulting in acute respiratory distress syndrome. This results from viral replication in lung epithelial cells causing cell injury, death, and a vigorous immune response. Developing a therapeutic that prevents viral replication is likely to significantly reduce lung disease in COVID-19 patients. Analysis of demographic data shows that cigarette smokers have a higher risk of severe COVID-19 disease and death. In the United States, cigarette smoking prevalence is significantly higher among people currently serving in the military than among the civilian population. The percentage of active duty military who ever smoked was highest during the Korean and Vietnam Wars (75%). Currently, overall 32.2% of active duty military personnel smoke versus 19.8% of adults in the civilian population and 22.2% of veterans. Given the risks of smoking and severe COVID-19 infection, and the high rates of smoking in the military, our military personnel and veterans are at higher risk for severe COVID-19 disease. We performed experiments on human airways directly exposed to cigarette smoke and then exposed them to the SARS-CoV-2. We found that there was a lot more infected cells after smoking than after no smoke exposure and that this could be explained by the virus hijacking the cellular machinery that was turned on by smoking. We performed a drug screen in regular cells and found a compound that inhibits this cell machinery, and we found that this significantly reduced viral infection in cells. This compound is already in clinical trials for cancer therapy and can be repurposed to treat COVID-19. The goal here is to test this promising drug in human lung models of viral infection to find out whether this drug will be effective in preventing the severe lung disease seen in some COVID-19 patients. We plan to also test this in a mouse model of human COVID-19 where the mice will have been exposed to cigarette smoke. The overall plan is to take all of the data showing how well the drug works to the U.S. Food and Drug Administration (FDA) to develop the compound towards a clinical trial. We envision this drug will be especially effective for preventing lung disease in current and former smokers and in this way will benefit all people but especially military personnel and veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110072
Entities
People
- Brigitte Gomperts
Organizations
- United States Army
- University of California, Los Angeles