Dataset Information

Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.

ABSTRACT: In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an investigational drug for acute myocardial infarction (MI) at clinical trial, obtained from healthy male subjects with molecular activity profiles in the Connectivity Map. We identified dyphilline, an FDA-approved drug for bronchial asthma, as a top ranked connection with LC28-0126. Subsequently, we demonstrated that LC28-0126 effectively ameliorates the pathophysiology of neutrophilic bronchial asthma in OVALPS-OVA mice accompanied with a reduction of inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), inhibition of the release of proinflammatory cytokines, relief of airway hyperactivity, and improvement of histopathological changes in the lung. Taken together, we suggest that LC28-0126 could be a potential therapeutic for bronchial asthma. In addition, this study demonstrated the potential general utility of computational drug repositioning using clinical profiles of the investigational drug.

SUBMITTER: Shin E

PROVIDER: S-EPMC4667219 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.

Shin Eunji E Lee Yong Chul YC Kim So Ri SR Kim Soon Ha SH Park Joonghoon J

Scientific reports 20151202

In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an in ...[more]

PMID: 26626943

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Project description:BACKGROUND:Improvements in asthma diagnosis and management require deeper understanding of the heterogeneity of the complex airway inflammation. We hypothesise that differences in the two major inflammatory phenotypes of asthma; eosinophilic and neutrophilic asthma, will be reflected in the lung protein expression profile of murine asthma models and can be delineated using proteomics of bronchoalveolar lavage (BAL). METHODS:BAL from mice challenged with ovalbumin (OVA/OVA) alone (standard model of asthma, here considered eosinophilic) or OVA in combination with endotoxin (OVA/LPS, model of neutrophilic asthma) was analysed using liquid chromatography coupled to high resolution mass spectrometry, and compared with steroid-treated animals and healthy controls. In addition, conventional inflammatory markers were analysed using multiplexed ELISA (Bio-Plex™ assay). Multivariate statistics was performed on integrative proteomic fingerprints using principal component analysis. Proteomic data were complemented with lung mechanics and BAL cell counts. RESULTS:Several of the analysed proteins displayed significant differences between the controls and either or both of the two models reflecting eosinophilic and neutrophilic asthma. Most of the proteins found with mass spectrometry analysis displayed a considerable increase in neutrophilic asthma compared with the other groups. Conversely, the larger number of the inflammatory markers analysed with Bio-Plex™ analysis were found to be increased in the eosinophilic model. In addition, major inflammation markers were correlated to peripheral airway closure, while commonly used asthma biomarkers only reflect central inflammation. CONCLUSION:Our data suggest that the commercial markers we are currently relying on to diagnose asthma subtypes are not giving us comprehensive or specific enough information. The analysed protein profiles allowed to discriminate the two models and may add useful information for characterization of different asthma phenotypes.

Dataset Information

Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.

Publications

Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.

Similar Datasets

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