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Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss

Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical...

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Autores principales: Schubert, Nick M. A., van Tuinen, Marcel, Pyott, Sonja J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028743/
https://www.ncbi.nlm.nih.gov/pubmed/35454087
http://dx.doi.org/10.3390/biom12040498
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author Schubert, Nick M. A.
van Tuinen, Marcel
Pyott, Sonja J.
author_facet Schubert, Nick M. A.
van Tuinen, Marcel
Pyott, Sonja J.
author_sort Schubert, Nick M. A.
collection PubMed
description Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea—the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC/SGN) and the stria vascularis and spiral ligament (SV/SL)—in young (6-week-old) and old (2-year-old) C57BL/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC/SGN or SV/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL.
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spelling pubmed-90287432022-04-23 Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss Schubert, Nick M. A. van Tuinen, Marcel Pyott, Sonja J. Biomolecules Article Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea—the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC/SGN) and the stria vascularis and spiral ligament (SV/SL)—in young (6-week-old) and old (2-year-old) C57BL/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC/SGN or SV/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL. MDPI 2022-03-25 /pmc/articles/PMC9028743/ /pubmed/35454087 http://dx.doi.org/10.3390/biom12040498 Text en © 2022 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
Schubert, Nick M. A.
van Tuinen, Marcel
Pyott, Sonja J.
Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title_full Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title_fullStr Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title_full_unstemmed Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title_short Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss
title_sort transcriptome-guided identification of drugs for repurposing to treat age-related hearing loss
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028743/
https://www.ncbi.nlm.nih.gov/pubmed/35454087
http://dx.doi.org/10.3390/biom12040498
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