Related Experiment Video
Updated: Jun 9, 2025
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data
Sara Saez-Atienzar1, Cleide Dos Santos Souza2, Ruth Chia3
1Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Department of Neurology, Ohio State University, Columbus, OH 43210, USA.
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. VIDEO ABSTRACT.
Insights
Acamprosate shows neuroprotective effects for C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This drug repurposing strategy, guided by genomics, offers a potential new therapy for these complex neurodegenerative diseases.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- C9orf72 repeat expansions are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- The exact mechanisms driving neuronal death in C9orf72-related diseases are not fully understood, hindering therapeutic development.
- Genomic data analysis offers a promising avenue to uncover therapeutic strategies for complex neurodegenerative conditions.
Purpose of the Study:
- To identify potential therapeutic agents for C9orf72-related neurodegenerative diseases using a drug repurposing approach.
- To leverage genomic data and gene expression patterns to find treatments for C9orf72 carriers.
- To validate the neuroprotective efficacy of identified drug candidates in relevant models.
Main Methods:
- An agnostic drug repurposing screen was conducted using a large dataset of genomic data from ALS and healthy individuals, including C9orf72 carriers.
- Gene and expression pattern matching, alongside analysis of genetic variants affecting onset age in C9orf72 carriers, guided the drug identification process.
- Neuroprotective effects of candidate drugs were validated in cellular models, with efficacy compared to riluzole.
Main Results:
- Acamprosate, a gamma-aminobutyric acid analog, was identified as a potential repurposed drug for C9orf72 repeat expansion carriers.
- Acamprosate demonstrated significant neuroprotective effects in cell models.
- The efficacy of acamprosate was found to be comparable to riluzole, the current standard of care for ALS.
Conclusions:
- Genomic-driven drug repurposing is a valuable strategy for complex neurodegenerative diseases like C9orf72-related ALS and FTD.
- Acamprosate represents a promising therapeutic candidate for patients with C9orf72 repeat expansions.
- Further research into acamprosate's mechanisms and clinical efficacy is warranted for C9orf72-related neurodegeneration.
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