Therapeutic application of alpha-1-antitrypsin in COVID-19

RationaleThe treatment options for COVID-19 patients are sparse and do not show sufficient efficacy. Alpha-1-antitrypsin (AAT) is a multi-functional host-defense protein with anti-proteolytic and anti-inflammatory activities. ObjectivesThe aim of the present study was to evaluate whether AAT is a suitable candidate for treatment of COVID-19. MethodsAAT and inflammatory markers were measured in the serum of COVID-19 patients. Human cell cultures were employed to determine the cell-based anti-protease activity of AAT and to test whether AAT inhibits the host cell entry of vesicular stomatitis virus (VSV) particles bearing the spike (S) protein of SARS-CoV-2 and the replication of authentic SARS-CoV-2. Inhaled and / or intravenous AAT was applied to nine patients with mild-to-moderate COVID-19. Measurements and Main ResultsThe serum AAT concentration in COVID-19 patients was increased as compared to control patients. The relative AAT concentrations were decreased in severe COVID-19 or in non-survivors in ratio to inflammatory blood biomarkers. AAT inhibited serine protease activity in human cell cultures, the uptake of VSV-S into airway cell lines and the replication of SARS-CoV-2 in human lung organoids. All patients, who received AAT, survived and showed decreasing respiratory distress, inflammatory markers, and viral load. ConclusionAAT has anti-SARS-CoV-2 activity in human cell models, is well tolerated in patients with COVID-19 and together with its anti-inflammatory properties might be a good candidate for treatment of COVID-19. FundingThis work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, the BMBF, the State of Lower Saxony, and The State of Saarland. Scientific Knowledge on the SubjectCOVID-19 is caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) and is a serious global health threat. Efficacious treatments are not available and there are no drugs that can prevent progression towards respiratory and extra-pulmonary organ failure. AAT has been studied in vitro and has activity against SARS-CoV-2. We searched PubMed and Google Scholar using the search terms "COVID-19", "SARS-CoV-2", "therapy", and "-1-antitrypsin" (AAT) for research published in 2020 and 2021. What This Study Adds to the FieldThis study shows the results of a translational program with a focus on the biology of AAT in COVID-19. The data show that there is a relative deficiency of AAT in relation to systemic inflammation. AAT inhibits serine protease activity in human airway cells and the replication of SARS-CoV-2 in human lung organoids. Inhaled and / or intravenous application of AAT in nine patients was associated with clinical stabilization. The findings of this exploratory study suggest that AAT has a mechanistic role in the pathophysiology of COVID-19 based on its anti-inflammatory and anti-viral activities. This offers the possibility to test and develop AAT application for treatment of different phenotypes or stages of COVID-19, including severe, inflammatory courses or early stages. Inhaled treatment could be an option to administer AAT non-invasively in early stages.