Therapeutic strategies for C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia

Purpose of review An intronic G(4)C(2) 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 G(4)C(2) 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. 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.

Automated summary

An intronic G(4)C(2) expansion mutation in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Therapeutic strategies for these diseases primarily focus on reducing the toxic effects of mutant expansion RNAs or dipeptide repeat proteins (DPRs). Promising therapeutic strategies include promoting degradation of expansion transcripts, inhibiting nuclear export or silencing transcription, as well as immunotherapy to reduce DPRs.