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In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system still lacking a cure. Treatment typically focuses on slowing the progression and managing MS symptoms. Single-cell transcriptomics allows the investigation of the immune system—the key player in MS onset and development—i...

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Autores principales: Shevtsov, Andrey, Raevskiy, Mikhail, Stupnikov, Alexey, Medvedeva, Yulia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864606/
https://www.ncbi.nlm.nih.gov/pubmed/36674506
http://dx.doi.org/10.3390/ijms24020985
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author Shevtsov, Andrey
Raevskiy, Mikhail
Stupnikov, Alexey
Medvedeva, Yulia
author_facet Shevtsov, Andrey
Raevskiy, Mikhail
Stupnikov, Alexey
Medvedeva, Yulia
author_sort Shevtsov, Andrey
collection PubMed
description Multiple sclerosis (MS) is an autoimmune disease of the central nervous system still lacking a cure. Treatment typically focuses on slowing the progression and managing MS symptoms. Single-cell transcriptomics allows the investigation of the immune system—the key player in MS onset and development—in great detail increasing our understanding of MS mechanisms and stimulating the discovery of the targets for potential therapies. Still, de novo drug development takes decades; however, this can be reduced by drug repositioning. A promising approach is to select potential drugs based on activated or inhibited genes and pathways. In this study, we explored the public single-cell RNA data from an experiment with six patients on single-cell RNA peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid cells (CSF) of patients with MS and idiopathic intracranial hypertension. We demonstrate that AIM2 inflammasome, SMAD2/3 signaling, and complement activation pathways are activated in MS in different CSF and PBMC immune cells. Using genes from top-activated pathways, we detected several promising small molecules to reverse MS immune cells’ transcriptomic signatures, including AG14361, FGIN-1-27, CA-074, ARP 101, Flunisolide, and JAK3 Inhibitor VI. Among these molecules, we also detected an FDA-approved MS drug Mitoxantrone, supporting the reliability of our approach.
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spelling pubmed-98646062023-01-22 In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data Shevtsov, Andrey Raevskiy, Mikhail Stupnikov, Alexey Medvedeva, Yulia Int J Mol Sci Article Multiple sclerosis (MS) is an autoimmune disease of the central nervous system still lacking a cure. Treatment typically focuses on slowing the progression and managing MS symptoms. Single-cell transcriptomics allows the investigation of the immune system—the key player in MS onset and development—in great detail increasing our understanding of MS mechanisms and stimulating the discovery of the targets for potential therapies. Still, de novo drug development takes decades; however, this can be reduced by drug repositioning. A promising approach is to select potential drugs based on activated or inhibited genes and pathways. In this study, we explored the public single-cell RNA data from an experiment with six patients on single-cell RNA peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid cells (CSF) of patients with MS and idiopathic intracranial hypertension. We demonstrate that AIM2 inflammasome, SMAD2/3 signaling, and complement activation pathways are activated in MS in different CSF and PBMC immune cells. Using genes from top-activated pathways, we detected several promising small molecules to reverse MS immune cells’ transcriptomic signatures, including AG14361, FGIN-1-27, CA-074, ARP 101, Flunisolide, and JAK3 Inhibitor VI. Among these molecules, we also detected an FDA-approved MS drug Mitoxantrone, supporting the reliability of our approach. MDPI 2023-01-04 /pmc/articles/PMC9864606/ /pubmed/36674506 http://dx.doi.org/10.3390/ijms24020985 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shevtsov, Andrey
Raevskiy, Mikhail
Stupnikov, Alexey
Medvedeva, Yulia
In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title_full In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title_fullStr In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title_full_unstemmed In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title_short In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data
title_sort in silico drug repurposing in multiple sclerosis using scrna-seq data
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864606/
https://www.ncbi.nlm.nih.gov/pubmed/36674506
http://dx.doi.org/10.3390/ijms24020985
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