Drug Repurposing to Treat Glucocorticoid Resistance in Asthma.

Alberta L Wang,Deborah A Meyers,Scott T Weiss,Alvin T Kho,Eugene R Bleecker,Quan Lu,Ronald Panganiban,Weiliang Qiu,Kelan G Tantisira,Geoffrey Chupp

doi:10.3390/jpm11030175

Abstract

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.

Highlights

Licensee MDPI, Basel, Switzerland.Asthma is one of the most common chronic respiratory diseases worldwide affecting more than 339 million children and adults [1]
Immortalized B cells were cultured from 145 subjects randomized to inhaled budesonide, and the subjects were divided into tertiles based on Inhaled corticosteroids (ICS) response measured by the change in percent predicted forced expiratory volume in one second (FEV1 ) from baseline at enrollment to month two on inhaled budesonide (Figure S1a) [25]
Childhood Asthma Management Program (CAMP) was composed of children (mean age 8.7 (±2.2) years) with mostly moderate persistent asthma

Summary

Introduction

Asthma is one of the most common chronic respiratory diseases worldwide affecting more than 339 million children and adults [1]. Inhaled corticosteroids (ICS) are considered one of the primary treatments for the control of asthma. Up to 30–50% of asthmatics have poor response to corticosteroid treatment [2,3]. Corticosteroid refractory asthma represents about 50% of total costs for treating asthma [4]. While the new generation biologics may help to address the issue of corticosteroid resistance, they remain

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