A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects.
Michael D Davis, Tatiana M Clemente, Olivia K Giddings, Kristie Ross, Rebekah S Cunningham, Laura Smith, Edward Simpson, Yunlong Liu, Kirsten Kloepfer, I Scott Ramsey, Yi Zhao, Christopher M Robinson, Stacey D Gilk, Benjamin Gaston
Author Information
Michael D Davis: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
Tatiana M Clemente: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
Olivia K Giddings: Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
Kristie Ross: Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
Rebekah S Cunningham: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
Laura Smith: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
Edward Simpson: Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana.
Yunlong Liu: Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana.
Kirsten Kloepfer: Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana.
I Scott Ramsey: Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia.
Yi Zhao: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
Christopher M Robinson: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
Stacey D Gilk: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
Benjamin Gaston: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine. begaston@iu.edu.
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 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: We grew primary 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 Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with 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 h and 120 h, relative to placebo, on both plaque assay and N protein expression ( < .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 pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard 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.
