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RNA sequencing of sputum cells from a phase IIa placebo controlled clinical trial of Risankizumb in severe asthma

ABSTRACT: Interleukin (IL)-23 is implicated in T2 and T17-mediated airway inflammation, supporting a role in asthma. We undertook a Phase II, randomized, double-blind, placebo-controlled, 24-week, parallel-group, multicenter trial to assess the efficacy and safety of risankizumab, an IL23p19 monoclonal antibody, administered subcutaneously (90 mg 4 weekly) in adults with severe asthma. Sputum samples were collected at several timepoints: visit 1B (week -3), visit 2 (week 0 proir to treatment), visit 7 (week 20), visit 8 (week 24, end of treatment), visit 12 (week 40, end of observation). RNA sequencing of sputum cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167074 | GEO | 2024/02/10

REPOSITORIES: GEO

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Project description:Background: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published. Methods: We conducted a genome-wide analysis of microRNA and messenger RNA (mRNA) in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis (WGCNA) was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes, and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway. Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for toll-like receptor (TLR) and Th17 signaling, and endoplasmic reticulum stress. Hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma. Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.

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RNA sequencing of sputum cells from a phase IIa placebo controlled clinical trial of Risankizumb in severe asthma

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