ALS — SOD1 antisense

Structural changes to the axon initial segment in presymptomatic ALS mice would impair motoneurones' ability to fire action potentials repetitively.

In adult presymptomatic G127X SOD1 mice, axon initial segments of alpha and gamma motoneurones were shorter (by 6.6% and 11.8%) and wider, yet in vivo intracellular recordings found no difference in single action potentials or in repetitive firing.

Why it matched: shares SOD1 · mechanism: Synaptic & neuronal function

Intrathecal antisense against the C9orf72 repeat expansion would lower dipeptide repeat protein throughout the CNS.

Poly(GP) fell sharply in lumbar CSF but post-mortem cortex from two participants showed near-baseline levels.

Why it matched: same research area · mechanism: Gene expression & RNA

Early clearance of amyloid plaques via monoclonal antibody would slow cognitive decline in prodromal patients.

Plaque burden dropped on PET imaging but ADAS-Cog scores showed no separation from placebo at 18 months.

Why it matched: mechanism: Synaptic & neuronal function · failed the same way: Target engaged, outcome unchanged · failed the same way: Intervened too late in the disease course

GSK-3 beta inhibition would reduce tau hyperphosphorylation and slow decline in mild-to-moderate Alzheimer's.

CSF p-tau181 dropped by 28% but ADAS-Cog showed no difference from placebo; the high-dose arm was halted for safety.

Why it matched: similar wording · failed the same way: Target engaged, outcome unchanged

A TREM2 agonist antibody would boost microglial plaque clearance and slow decline in early Alzheimer's.

Microglial activation markers rose and soluble TREM2 in CSF dropped, but CDR-SB scores were unchanged at 12 months.

Why it matched: similar wording · failed the same way: Target engaged, outcome unchanged