Resolve: C9orf72 ASO Treatment Reverses TDP-43 Pathology in ALS/FTD

Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=C9orf72). Hypothesis: Does antisense oligonucleotide (ASO) targeting C9orf72 repeat expansions reduce TDP-43 mislocalization and restore motor function in ALS/FTD? Success criteria: 1. C9-ASO reduces GGGGCC repeat RNA foci by >60% in patient-derived motor neurons (72h post-treatment). 2. TDP-43 nuclear localization (nuclear/cytoplasmic ratio by IF) restores to >85% of control levels. 3. Poly(GP) DPR protein levels decrease by >50% in CSF from ASO-treated rodents. 4. Motor function (grid walk, rotarod) improves by >35% in ASO-treated ALS mouse model.