ABSTRACT This application is to support a clinical trial of the first mRNA engineered cell therapy for Acute Respiratory Distress Syndrome (ARDS), including ARDS caused by COVID-19. The FDA has already reviewed the IND application and determined that the study may proceed. ARDS is a severe inflammatory respiratory failure that kills an estimated 80,000 Americans each year. 80% of ARDS patients require mechanical ventilation. No FDA-approved therapies for ARDS are available. ARDS may result from infectious or non-infectious (e.g., traumatic or chemical) insults. COVID-19 is currently the most common cause of ARDS, and the vast majority of COVID-19 deaths are due to ARDS. Neutrophil Extracellular Traps (NETs) drive the hyperactive inflammatory response in ARDS and COVID-19, and presence of NETs correlates strongly with ARDS severity. NETs are produced by locally-trafficked neutrophils undergoing NETosis, a programmed cell death where the cells lyse to secrete DNA decorated with inflammatory proteins. Low amounts of NETs are thought to help entrap infection, but hyperactivated neutrophils produce large quantities of NETs that cause hypoxia and immune thrombi due to physical blockade of alveoli and microvasculature. A NET-degrading therapy therefore would be a significant advance in treatment of ARDS. Descartes-30 is the first allogeneic (i.e., off-the-shelf) engineered human Mesenchymal Stem Cell (MSC) therapy secreting a combination of two potent NET-degrading enzymes. In this Phase 1/2a study, the hypothesis to be tested is that Descartes-30 will be well tolerated and show evidence of efficacy in patients with moderate to severe ARDS and COVID- 19. Aims are to determine the maximum tolerated dose and evidence of preliminary efficacy, define pharmacokinetic properties and biologic correlates of disease, and establish a validated Potency assay for use in later-stage clinical development. These data will inform the design of a controlled registration study in patients with moderate-to-severe ARDS.