The Polymenidou Lab at DQBM contributed to a new study in Science showing that selective inhibition of RAN translation rescues key features of C9ORF72-related ALS and FTD . By introducing a single nucleotide mutation in a CUG start codon upstream of the G4C2 repeat, the team blocked production of toxic dipeptide repeat proteins while preserving repeat RNA expression and RNA foci formation.
In mouse models, this strategy restored motor and cognitive performance, reduced TDP-43 pathology, neuroinflammation, STING activation, and plasma neurofilament light levels. CRISPR base editing in patient-derived iPSC neurons similarly reduced DPR production and improved survival and transcriptomic profiles.
The findings provide strong evidence that DPRs, rather than repeat RNAs, are the principal drivers of C9ORF72 ALS and FTD pathogenesis.
Publication: https://doi.org/10.1126/science.adv2600