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01-12-2020 | Expectoration | Research

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis

Authors: Mirco Govoni, Michele Bassi, Stefano Vezzoli, Germano Lucci, Aida Emirova, Marie Anna Nandeuil, Stefano Petruzzelli, Gera L. Jellema, Ebenezer K. Afolabi, Brendan Colgan, Brian Leaker, Oliver Kornmann, Kai Michael Beeh, Henrik Watz, Dave Singh

Published in: Respiratory Research | Issue 1/2020

Abstract

Background

Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis.

Methods

Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study.

Results

CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant.

Conclusions

Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects.

Trial registration

ClinicalTrial.gov, EudraCT, 2015–005550-35. Registered 15 July 2016.

Available only for authorised users

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Title: Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis
Authors: Mirco Govoni
Michele Bassi
Stefano Vezzoli
Germano Lucci
Aida Emirova
Marie Anna Nandeuil
Stefano Petruzzelli
Gera L. Jellema
Ebenezer K. Afolabi
Brendan Colgan
Brian Leaker
Oliver Kornmann
Kai Michael Beeh
Henrik Watz
Dave Singh
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Expectoration
Bronchitis
Cytokines
Chronic Obstructive Lung Disease
Published in: Respiratory Research / Issue 1/2020
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-020-1329-y

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