Therapeutic strategies for C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia
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Updated: Oct 24, 2025
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Guillaume M Hautbergue1,2,3, John D Cleary4,5,6, Shu Guo4,5,6
1Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield.
Purpose Of Review:
An intronic G4C2 expansion mutation in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Although there are currently no treatments for this insidious, fatal disease, intense research has led to promising therapeutic strategies, which will be discussed here.
Recent Findings:
Therapeutic strategies for C9-ALS/FTD have primarily focused on reducing the toxic effects of mutant expansion RNAs or the dipeptide repeat proteins (DPRs). The pathogenic effects of G4C2 expansion transcripts have been targeted using approaches aimed at promoting their degradation, inhibiting nuclear export or silencing transcription. Other promising strategies include immunotherapy to reduce the DPRs themselves, reducing RAN translation, removing the repeats using DNA or RNA editing and manipulation of downstream disease-altered stress granule pathways. Finally, understanding the molecular triggers that lead to pheno-conversion may lead to opportunities that can delay symptomatic disease onset.
Summary:
A large body of evidence implicates RAN-translated DPRs as a main driver of C9-ALS/FTD. Promising therapeutic strategies for these devastating diseases are being rapidly developed with several approaches already in or approaching clinical trials.
Insights
Researchers are exploring new treatments for C9-ALS/FTD, a fatal neurodegenerative disease caused by a C9orf72 gene mutation. Promising strategies target toxic RNA and proteins, with some therapies nearing clinical trials.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The C9orf72 gene mutation is the leading genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD).
- Currently, no effective treatments exist for C9-ALS/FTD, highlighting an urgent need for therapeutic interventions.
Purpose of the Study:
- To review and discuss promising therapeutic strategies for C9-ALS/FTD.
- To provide an overview of current research directions and potential treatments for this devastating disease.
Main Methods:
- Focus on reducing toxic effects of mutant G4C2 expansion RNAs and dipeptide repeat proteins (DPRs).
- Strategies include promoting RNA degradation, inhibiting nuclear export, silencing transcription, and immunotherapy.
- Other approaches involve reducing RAN translation, gene editing, and modulating stress granule pathways.
Main Results:
- Di-peptide repeat proteins (DPRs) generated through repeat-associated non-AUG (RAN) translation are key drivers of C9-ALS/FTD.
- Multiple therapeutic strategies are under active development.
- Several promising approaches are in or nearing clinical trials.
Conclusions:
- Intense research is yielding promising therapeutic strategies for C9-ALS/FTD.
- Targeting toxic RNA and DPRs offers potential for treating this fatal neurodegenerative condition.
- Understanding disease mechanisms may lead to interventions that delay symptom onset.
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