Saez-Atienzar, S., Souza, C.D.S., Chia, R. et al. (323 more authors) (2024) Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data. Cell Genomics, 4 (11). 100679. ISSN 2666-979X
Abstract
Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | C9orf72; acamprosate; age at onset; amyotrophic lateral sclerosis; drug repurposing; frontotemporal dementia; translation; Humans; C9orf72 Protein; Amyotrophic Lateral Sclerosis; Drug Repositioning; Frontotemporal Dementia; Genomics; Riluzole; Male; Female; Neuroprotective Agents; DNA Repeat Expansion |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/V000470/1 MEDICAL RESEARCH COUNCIL MR/V027735/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Feb 2025 15:45 |
Last Modified: | 10 Feb 2025 15:45 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.xgen.2024.100679 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:223127 |
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