Chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide repeat expansion (C9ORF72 HRE)

The Chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide repeat expansion is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation consists of an abnormally large number of GGGGCC (G4C2) repeats within the first intron of the C9ORF72 gene, typically ranging from hundreds to thousands of units in affected individuals. Pathogenesis is attributed to a combination of toxic gain-of-function 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—and a loss-of-function effect due to reduced expression of the endogenous C9ORF72 protein. Therapeutic development has largely focused on antisense oligonucleotides (ASOs) designed to selectively degrade repeat-containing transcripts, as well as small molecules aimed at stabilizing G-quadruplex structures or inhibiting RAN translation. Despite the promise of these approaches, recent clinical trials have encountered significant hurdles, highlighting the complexity of balancing the reduction of toxic products with the preservation of normal C9ORF72 function. Biomarkers such as CSF poly(GP) levels are currently utilized to monitor target engagement and therapeutic efficacy in clinical settings.

Other names

C9ORF72 HREGGGGCC repeat expansionG4C2 repeat expansionC9ALS/FTD expansionC9ORF72 hexanucleotide repeat

Antisense oligonucleotide-mediated RNA degradation, inhibition of repeat-associated non-AUG (RAN) translation, G-quadruplex stabilization, and CRISPR-mediated gene excision.