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

Repeat-expanded C9orf72 transcripts are pathological RNA molecules containing an abnormally long hexanucleotide (G4C2) repeat expansion within the first intron of the C9orf72 gene (NIH, 2023). This genetic alteration is the most frequent cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (PubMed, 2021). The expanded transcripts exert neurotoxicity through a gain-of-function mechanism, forming nuclear RNA foci that sequester essential RNA-binding proteins (Nature Reviews Neurology, 2022). Additionally, these transcripts undergo repeat-associated non-AUG (RAN) translation, producing toxic dipeptide repeat proteins (DPRs) such as poly-GP and poly-GR. These DPRs and RNA foci disrupt critical cellular processes, including nucleocytoplasmic transport and RNA metabolism. Therapeutic interventions, particularly antisense oligonucleotides (ASOs), are designed to selectively bind and degrade these expanded transcripts to mitigate toxicity (Science Translational Medicine, 2022). While clinical trials for early candidates like BIIB078 and WVE-004 did not meet primary endpoints, the target remains a central focus for precision medicine in neurodegeneration (Biogen, 2022; Wave Life Sciences, 2023). Monitoring efficacy often involves measuring DPR levels in the cerebrospinal fluid as a direct biomarker of target engagement.

Other names

C9orf72 G4C2 repeat expansionC9orf72 sense and antisense transcriptsG4C2 repeat-containing RNAC9orf72 HRE RNA

Antisense oligonucleotides (ASOs) target the G4C2 repeat-containing transcripts for RNase H-mediated degradation, thereby reducing the levels of toxic RNA foci and dipeptide repeat proteins (DPRs).