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A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects.
Davis, Michael D; Clemente, Tatiana M; Giddings, Olivia K; Ross, Kristie; Cunningham, Rebekah S; Smith, Laura; Simpson, Edward; Liu, Yunlong; Kloepfer, Kirsten; Ramsey, I Scott; Zhao, Yi; Robinson, Christopher M; Gilk, Stacey D; Gaston, Benjamin.
  • Davis MD; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
  • Clemente TM; Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana.
  • Giddings OK; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
  • Ross K; Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
  • Cunningham RS; Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
  • Smith L; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
  • Simpson E; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
  • Liu Y; Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana.
  • Kloepfer K; Department of BioHealth Informatics, School of Informatics and Computing, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana.
  • Ramsey IS; Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana.
  • Zhao Y; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
  • Robinson CM; Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana.
  • Gilk SD; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia.
  • Gaston B; Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
Respir Care ; 66(1): 113-119, 2021 01.
Article in English | MEDLINE | ID: covidwho-1389654
Semantic information from SemMedBD (by NLM)
1. Inspiration function PROCESS_OF Healthy Volunteers
Subject
Inspiration function
Predicate
PROCESS_OF
Object
Healthy Volunteers
2. Inspiration function ASSOCIATED_WITH airway disease
Subject
Inspiration function
Predicate
ASSOCIATED_WITH
Object
airway disease
3. 2019 novel coronavirus PROCESS_OF Homo sapiens
Subject
2019 novel coronavirus
Predicate
PROCESS_OF
Object
Homo sapiens
4. plaque assay MEASURES Virus Replication
Subject
plaque assay
Predicate
MEASURES
Object
Virus Replication
5. plaque assay METHOD_OF Placebos
Subject
plaque assay
Predicate
METHOD_OF
Object
Placebos
6. Infectious Lung Disorder PROCESS_OF Patients
Subject
Infectious Lung Disorder
Predicate
PROCESS_OF
Object
Patients
7. Inspiration function PROCESS_OF Healthy Volunteers
Subject
Inspiration function
Predicate
PROCESS_OF
Object
Healthy Volunteers
8. Inspiration function ASSOCIATED_WITH airway disease
Subject
Inspiration function
Predicate
ASSOCIATED_WITH
Object
airway disease
9. 2019 novel coronavirus PROCESS_OF Homo sapiens
Subject
2019 novel coronavirus
Predicate
PROCESS_OF
Object
Homo sapiens
10. plaque assay MEASURES Virus Replication
Subject
plaque assay
Predicate
MEASURES
Object
Virus Replication
11. plaque assay METHOD_OF Placebos
Subject
plaque assay
Predicate
METHOD_OF
Object
Placebos
12. Infectious Lung Disorder PROCESS_OF Patients
Subject
Infectious Lung Disorder
Predicate
PROCESS_OF
Object
Patients
ABSTRACT

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 (P < .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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Epithelial Cells / SARS-CoV-2 / COVID-19 / Glycine / Isotonic Solutions / Lung Type of study: Controlled clinical trial / Randomized controlled trials Limits: Humans Language: English Journal: Respir Care Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Epithelial Cells / SARS-CoV-2 / COVID-19 / Glycine / Isotonic Solutions / Lung Type of study: Controlled clinical trial / Randomized controlled trials Limits: Humans Language: English Journal: Respir Care Year: 2021 Document Type: Article