This board replaces the “29,625 hypotheses” vanity metric per Phase 1 of the breakthrough plan. The platform’s job is killing or proving fast, not accumulating.
Every entry below carries an explicit kill criterion, a required experiment, and a current claim-state on the six-state ladder. None has yet been experimentally validated. The full 29K hypothesis archive remains available at /hypotheses/ (research-grade signal, not validated leads).
— Synthesised from the 3-LLM cross-review (ChatGPT + Gemini + Claude Opus) and the locked breakthrough plan v2.
Stabilization of the agrin-LRP4-MuSK-DOK7 ternary signalling complex restores neuromuscular-junction integrity in SMA. The complex is dynamic, multi-protein, underserved by classical structural biology — exactly where a multi-model AI consensus stack (AF3 + Boltz-2 + Chai-1 + NeuralPLexer-3) gives an edge over Roche / Biogen / Novartis. Whitespace target: SMN-independent, NMJ-stability-axis.
Required experiment
iPSC patient-derived motor neuron + myotube co-culture; readout: AChR clustering area, synapse count, MN survival, calcium activity, neurite length. CRO partnership scheduled Phase 3.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No measurable AChR cluster size increase AND no MN survival benefit on top of risdiplam standard-of-care after 14-day exposure.
AGRN-LRP4 binding triggers MuSK clustering and AChR aggregation at the synapse. Stabilizing this initial step rescues NMJ maturation in patient iPSC motor neurons. Antibody-class candidate (ARGX-119 / adimanebart) under industry development for neuromuscular disease.
Required experiment
iPSC patient-derived MN + myotube co-culture + LRP4-stabilizing antibody panel. Readouts: synapse maturation kinetics, AChR cluster size, miniature endplate potentials.
Refuting / contradicting (3)
Kill criterion (falsifies the hypothesis)
No synapse-maturation acceleration vs vehicle in patient iPSC NMJ within 21-day differentiation window.
Latent myostatin antagonism rescues residual muscle weakness in SMA patients already receiving SMN restoration. SAPPHIRE Phase-3 hit endpoints (Lancet Neurology 2025), opening the lane for orally bioavailable small-molecule myostatin antagonists.
Required experiment
SMA Δ7 mouse on nusinersen + apitegromab analog vs nusinersen alone. Readouts: grip strength, motor-function score, muscle mass, lifespan.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No incremental motor-function gain vs nusinersen-alone arm at 90-day endpoint (paired study, n ≥ 8 per arm).
STMN2 (Stathmin-2) regulates axonal microtubule dynamics. Restoring STMN2 splicing or expression rescues axonal length and branching in SMA motor neurons. Open whitespace — TDP-43 + STMN2 axis dominant in ALS literature, underexplored in SMA.
Required experiment
Patient iPSC motor neurons + STMN2 splice-rescue ASO panel. Readouts: full-length STMN2 transcript fraction, axon length, axon branching, retrograde transport.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No axon-length or axon-branching rescue in patient MNs at 14-day exposure to STMN2 splice-rescue ASO.
RNA-protein-ligand ternary complex modulators of SMN2 splicing (risdiplam-class). Technical capability moat — running AF3 + Boltz-2 in proper RNA-protein-ligand ternary mode is what separates our platform from the field.
Required experiment
SMN2 minigene splice-rescue assay in patient fibroblasts + AF3-ternary-predicted ligand panel. Readouts: full-length SMN2 transcript fold-increase, SMN protein increase, MN survival.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No SMN2 full-length transcript increase ≥ 1.5× over vehicle for any AF3-nominated ligand at 1 µM (panel of 8 nominations).
The ρ-ROCK-LIMK-Cofilin pathway controls actin dynamics; actin pathway dysregulation is triple-validated in SMA transcriptomic data (GSE287257, GSE290979, GSE255215). Specific-compound rescue claims (Fasudil, ripasudil) are PENDING re-verification per QMS audit. Axis-level hypothesis remains open; specific-paper evidence requires re-audit before re-citation.
Required experiment
iPSC patient-derived MN + ROCK inhibitor (Fasudil, ripasudil, Y-27632) panel. Readouts: actin polymerization, AChR clustering, MN survival.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No AChR-cluster rescue with any ROCK inhibitor at 1-10 µM in patient iPSC MNs (panel of 3 compounds, n ≥ 4 per condition).
Risdiplam (or nusinersen, or onasemnogene) PLUS a hit from the NMJ-rescue lane (Top-10 #1 or #2). Hypothesis: additive synaptic-density and motor-function rescue beyond SMN restoration alone.
Required experiment
iPSC patient MN + myotube co-culture; arm A: risdiplam alone, arm B: NMJ-rescue compound alone, arm C: combo. Readouts: AChR cluster density, mEPP frequency, MN survival.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No additive AChR cluster density (≥ 1.5× over either arm alone) at any tested combo concentration.
SMN therapy plus apitegromab-class myostatin antagonist. Direct extrapolation from SAPPHIRE Phase-3 design.
Required experiment
SMA Δ7 mouse, n=8 per arm: nusinersen alone, myostatin-antagonist alone, combo. Readouts: grip strength, treadmill, lifespan.
Refuting / contradicting (5)
Kill criterion (falsifies the hypothesis)
No incremental grip-strength gain ≥ 15% over nusinersen-alone arm at 90-day endpoint.
SMN therapy plus a hit from the actin-axis lane (Top-10 #6, #4 STMN2). Hypothesis: synergistic neurite + axonal preservation beyond SMN-directed therapy alone.
Required experiment
iPSC patient MN; arm A: risdiplam, arm B: STMN2-rescue ASO, arm C: combo. Readouts: axon length, branching density, MN survival.
Refuting / contradicting (0)
No refuting papers attached — actively searching.
Kill criterion (falsifies the hypothesis)
No additive axon-length or branching density vs either arm alone.
NRF2 antioxidant response activators (e.g. dimethyl fumarate, omaveloxolone) rescue oxidative-stress phenotype in SMA motor neurons. Existing approved drugs in adjacent indications (MS, Friedreich's ataxia) provide a fast translation path.
Required experiment
iPSC patient MN under oxidative stress + dimethyl fumarate / omaveloxolone panel. Readouts: ROS levels, glutathione, MN survival.
Refuting / contradicting (4)
Kill criterion (falsifies the hypothesis)
No oxidative-phenotype rescue (ROS ≥ 30% reduction OR survival ≥ 20% improvement) at any tested concentration.