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Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning.

ABSTRACT: In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments.

SUBMITTER: Olla S

PROVIDER: S-EPMC8705550 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveFinding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells.Materials and methodsBased 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.ResultsWe 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.ConclusionWe 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.

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Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning.

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