Mechanistic description
Antisense oligonucleotides targeting expanded GGGGCC repeats in C9orf72 offer the strongest therapeutic hypothesis by simultaneously addressing three pathogenic mechanisms: C9orf72 haploinsufficiency, RNA foci sequestration, and toxic dipeptide repeat protein accumulation. The tofersen precedent validates the ASO modality for motor neuron disease, and ongoing clinical trials (NCT03626012) provide immediate translational momentum. Critical risks include cortical delivery limitations for FTD pathology and potential immune dysfunction from C9orf72 loss.
Evidence for (3)
C9orf72 expansion is most common genetic cause of familial ALS/FTD
DPR proteins cause toxicity in flies and mouse models
ASOs reduce C9 transcripts and DPRs in patient-derived neurons
Evidence against (2)
C9orf72 KO mice show immune/lysosomal defects suggesting haploinsufficiency risk
DPR levels don't always correlate with disease severity