Translational insights into Duchenne muscular dystrophy: network biomarker identification and drug repositioning through multi-omics approaches

Abstract

Aim: Duchenne muscular dystrophy (DMD) is a rare genetic condition that results in a lack of dystrophin protein due to a series of mutations. Current treatment strategies for DMD remain limited, highlighting the urgent need for novel therapeutic options. This study aimed to identify drugs that can be repositioned using DMD-specific molecular network signatures and potential diagnostic biomarkers, using a holistic, multi-omics data-integration approach.

Methods: We have examined messenger RNA expression datasets GSE109178, GSE70955, and GSE38417 to identify differentially expressed genes (DEGs) using adjusted P-value < 0.001 and |log₂(fold change)| > 1 as the cut-off criteria. A total of 285 DEGs were identified as common across all three datasets. Principal component analyses were carried out using 33 hub genes identified from three-layered (protein-protein interaction, transcription factor, and microRNA) biological network constructions.

Results: The discrimination effect of these hub genes was found to be significantly higher between DMD patients and healthy controls. Therefore, these hub genes might be proposed as potential DMD-specific network biomarkers. Also, a drug repositioning analysis was conducted, revealing that celastrol, emetine dihydrochloride hydrate, radicicol, withaferin-A, and apigenin triacetate were reported as potential drugs for the management of DMD pathogenesis. The docking analysis with these repositioned drug candidates showed significant binding affinities among 17 network biomarkers (SQSTM1, PML, SPTAN1, SPTBN1, KIAA1429, SOX4, SP1, SPP1, NFKB1, TP53, NKX3-1, CIITA, ARL6IP1, IGFBP5, OCIAD2, RAP2B, and NFIB).

Conclusion: Celastrol and emetine dihydrochloride hydrate were the two repurposed small molecules that demonstrated effective docking results compared with inhibitors of hub genes and with the clinically used DMD-specific drug vamolorone. Further studies should be conducted to recapitulate these findings through in vitro and in vivo studies.

Keywords

Transcriptomics / Duchenne muscular dystrophy / drug repositioning / celastrol / emetine

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