C9orf72 hexanucleotide repeat expansion (C9orf72 HRE)

The expanded C9orf72 GGGGCC hexanucleotide repeat is the most prevalent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). In healthy individuals, the C9orf72 gene typically contains fewer than 25-30 copies of this hexanucleotide sequence, whereas affected patients may harbor hundreds or thousands of repeats. This expansion leads to neurodegeneration through multiple toxic mechanisms, including the formation of nuclear RNA foci that sequester essential RNA-binding proteins and the production of toxic dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation (Gendron et al., 2017). Additionally, the expansion can lead to a reduction in the expression of the normal C9orf72 protein, which is involved in endosomal trafficking and autophagy. Therapeutic strategies have primarily focused on antisense oligonucleotides (ASOs) designed to selectively degrade repeat-containing transcripts to mitigate gain-of-function toxicity (Biogen, 2022). Despite the failure of early clinical candidates like BIIB078 and WVE-004 to show clinical benefit in Phase 1 trials, the target remains a central focus for developing precision therapies for neurodegenerative diseases (Wave Life Sciences, 2023).

Other names

GGGGCC repeat expansionG4C2 repeatC9orf72 G4C2 expansionC9-ALS/FTD mutationExpanded C9orf72 GGGGCC hexanucleotide repeat–containing nucleic acid

Antisense oligonucleotides (ASOs) target the GGGGCC repeat-containing transcripts for RNase H-mediated degradation, reducing the levels of toxic RNA foci and dipeptide repeat proteins (DPRs) while ideally sparing the wild-type mRNA (Biogen, 2022; Wave Life Sciences, 2023).