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Lookup NU author(s): Dr Polina YarovaORCiD, Dr Seva TelezhkinORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society for Pharmacology and Experimental Therapy, 2021.
For re-use rights please refer to the publisher's terms and conditions.
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics. Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine–induced AHR in naïve mice and suppressed both AHR and airway inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate, or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, pharmacokinetics/pharmacodynamics, formulation, and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe, and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation, and abrogating some features of airway remodeling.
Author(s): Yarova PL, Huang P, Schepelmann MW, Bruce R, Ecker R, Nica R, Telezhkin V, Traini D, dos Reis LG, Kidd EJ, Ford WR, Broadley KJ, Kariuki BM, Corrigan CJ, Ward JPT, Kemp PJ, Riccardi D
Publication type: Article
Publication status: Published
Journal: Journal of Pharmacology and Experimental Therapeutics
Year: 2021
Volume: 376
Issue: 1
Pages: 51-63
Print publication date: 01/01/2021
Online publication date: 28/10/2020
Acceptance date: 05/10/2020
Date deposited: 04/11/2021
ISSN (print): 0022-3565
ISSN (electronic): 1521-0103
Publisher: American Society for Pharmacology and Experimental Therapy
URL: https://doi.org/10.1124/jpet.120.000281
DOI: 10.1124/jpet.120.000281
PubMed id: 33115824
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