Preprint Watch 2026-10-15: 1 Clinical Failures Flagged for SOD1 | Claidex

Claidex Preprint Watch

doi:10.1101/2025.10.17.682996

Preprint WatchModerateOctober 15th, 2026

Preemptive SOD1 Silencing via Neonatal Intramuscular AAV Therapy Modifies Disease Trajectory in an ALS Mouse Model

Gong, X.; Xie, Y.; Wang, W.; Xu, T.

Neonatal intramuscular delivery of an rAAV2-retro vector silencing SOD1 modifies disease trajectory in an ALS mouse model, positioning preemptive presymptomatic silencing and retrograde delivery as the determinants of benefit rather than the choice of target.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The mechanistic claim is about timing and delivery rather than target choice: silencing SOD1 before symptom onset, through retrograde transport from muscle, changes the disease course in a mouse model. Claidex records mt-1186-oral-edaravone-sod1-als-phase3-futility, a Phase 3 stopped for futility in symptomatic patients, and that contrast is the point of the flag. A presymptomatic intervention in a mouse carrying a defined SOD1 mutation and a symptomatic trial of a small molecule in genetically unselected patients are not the same experiment, and the preprint offers no human data. The flag is raised because the Claidex record for this target is an efficacy failure, which sets the prior any new SOD1 programme has to argue against, and because the preprint implicitly concedes that intervention timing is the variable that matters.

Abstract excerpt

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder with limited therapeutic options. Mutations in the gene encoding superoxide dismutase 1 (SOD1) represent a major genetic cause of familial ALS, driving motor neuron degeneration through toxic gain-of-function mechanisms. Although gene silencing approaches targeting SOD1 show substantial therapeutic potential, their clinical translation remains restricted by suboptimal delivery to the spinal motor neurons and safety concerns linked to conventional viral vectors. This study presents a minimally invasive gene therapy strategy that combines the retrograde transport capability of rAAV2-retro with the safety of an artificial microRNA (miRNA) to achieve pan-spinal SOD1 silencing. A single intramuscular injection of rAAV2-retro-miRNA into neonatal SOD1G93A mice resulted in widespread transduction of spinal motor neurons, significant reduction of mutant SOD1 protein, and multifaceted therapeutic benefits. Treated mice exhibited delayed disease onset, extended lifespan, preserved motor function, reduced neuroinflammation, and protection of neuromuscular junctions and spinal motor neurons. Importantly, the artificial miRNA construct demonstrated a superior safety profile relative to short hairpin RNA (shRNA)-based constructs, which induced marked toxicity and lethality in wild-type mice. These findings establish neonatal intramuscular delivery of rAAV2-retro-miRNA as a safe, efficient, and clinically translatable strategy for preemptive intervention in SOD1-mediated ALS, offering broader applicability to other motor neuron diseases.

Matching Claidex post-mortems

1 of 1 indexed

May 23, 2026MT-1186 oral edaravone in ALS: a Phase 3b extension follows its parent into futilityMT-1186 (oral edaravone)EfficacyMRS 33

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.