Chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 HRE)

The Chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion is a genetic mutation characterized by the pathological repetition of a GGGGCC sequence within the first intron of the C9orf72 gene (DeJesus-Hernandez et al., Neuron, 2011). While healthy individuals typically carry fewer than 25-30 repeats, affected patients may possess hundreds or thousands, making it the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Renton et al., Neuron, 2011). The expansion causes disease through three primary mechanisms: loss of C9orf72 protein function (haploinsufficiency), the formation of toxic RNA foci that sequester essential RNA-binding proteins, and the unconventional repeat-associated non-AUG (RAN) translation of the expansion into toxic dipeptide repeat proteins (DPRs) (Taylor et al., Nature Reviews Neurology, 2017). Therapeutic strategies focus on reducing the levels of these toxic sense and antisense expansion-containing transcripts, primarily using antisense oligonucleotides (ASOs) or small molecules. Although clinical candidates like BIIB078 and WVE-004 have faced recent setbacks in clinical trials, the target remains a central focus of neurodegenerative disease research (Biogen, 2022; Wave Life Sciences, 2023). Effective drug development requires a precise balance between degrading the toxic repeat-containing RNA and maintaining sufficient levels of the endogenous C9orf72 protein to support normal cellular functions like autophagy and endosomal trafficking.

Other names

GGGGCC repeat expansionG4C2 repeat expansionC9orf72 repeatC9ALS/FTD locus

Antisense oligonucleotide-mediated RNA degradation, RNA interference (RNAi), Small molecule inhibition of RAN translation, CRISPR-Cas9 gene editing, and RNA-binding protein displacement.