Immune cells transcriptome-based drug repositioning for multiple sclerosis.

Abstract

Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells. Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We obtained 50 hub target genes for CD4+ T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19+ B cells and 15 target pathways for CD4+ T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways. We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.