RT Journal Article
SR Electronic
T1 A treatment that eliminates SARS-CoV-2 replication in human airway epithelial cells and is safe for inhalation as an aerosol in healthy human subjects.
JF Respiratory Care
FD American Association for Respiratory Care
SP respcare.08425
DO 10.4187/respcare.08425
A1 Michael D. Davis
A1 Tatiana M. Clemente
A1 Olivia K. Giddings
A1 Kristie Ross
A1 Rebekah S. Cunningham
A1 Laura Smith
A1 Edward Simpson
A1 Yunlong Liu
A1 Kirsten Kloepfer
A1 I. Scott Ramsey
A1 Yi Zhao
A1 Christopher M. Robinson
A1 Stacey D. Gilk
A1 Benjamin Gaston
YR 2020
UL http://rc.rcjournal.com/content/early/2020/09/22/respcare.08425.abstract
AB Background: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense and worsens airway inflammation. Inhaled Optate is designed to safely to raise airway surface pH and is well-tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms.Methods: Here, we grew primary normal human airway epithelial (NHAE) cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether it would prevent viral infection and replication. Cells were pre-treated with Optate or placebo prior to infection (MOI of 0.1) and viral replication was determined by plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial.Results: Optate almost completely prevented viral replication at each time point between 24 and 120 hours, relative to placebo, both by plaque assay and by N protein expression (p < 0.001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs or oxygenation.Conclusions: Inhaled Optate may be well-suited for a clinical trial in patients with a pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regards to pH, isotonicity and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.