SMA Congress 2026: NMJ axis is the #1 unmet need — launching an in-silico rescue campaign
What the 2026 SMA Congress told us
The 5th International Scientific Congress on SMA (Budapest, 11–14 March 2026) reframed the agrin-LRP4-MuSK-DOK7-RAPSN NMJ axis as the #1 unmet need in SMA therapeutics. Multiple talks (WS1, WS12, O27, O28 Vanhauwaert, O42 Donadio) converge on one point: NMJ defects persist even under SMN-upregulating therapies. The field is moving from "restore SMN" to "restore SMN and stabilise the NMJ".
The headline clinical story is argenx ARGX-119 — a first-in-class MuSK agonist Fab that directly activates the kinase without blocking endogenous agrin. In preclinical DOK7-CMS mice ARGX-119 reverses disease relapse; combined with SMN2 splice modulators in SMA mice it improves strength beyond what SMN restoration delivers alone (O28 Vanhauwaert, PMID 39292800).
The axis, in structural terms
| Target | UniProt | Role | PDB |
|---|---|---|---|
| MuSK | O15146 | Receptor tyrosine kinase, activated trans by agrin-LRP4 | 8S9P ternary complex cryo-EM |
| LRP4 | O75096 | β-propeller scaffold bridging agrin to MuSK | 3V64 agrin-LRP4 |
| DOK7 | Q18PE1 | PH-PTB adapter, dimerises pY553-MuSK | 3ML4 PH domain |
| AGRN | O00468 | Motor-neuron-derived inducer, z+-spliced LG3 | 3V64 LG3-LRP4 |
| RAPSN | Q13702 | 7-TPR scaffold clustering AChRs | 4BOO |
Our campaign
We have seeded these five targets into the platform and are launching a DiffDock screen against:
- MuSK kinase intracellular domain (trans-autophosphorylation pocket)
- DOK7 PH-PTB tandem (dimerisation interface)
- LRP4 β-propeller 1 (agrin NxI-motif binding site)
- AGRN LG3 (LRP4 binding surface)
- RAPSN TPR scaffold (allosteric)
...with a compound library that includes ARGX-119-like scaffolds, salbutamol, amifampridine (3,4-DAP), pyridostigmine, arimoclomol, and the ChEMBL kinase library. Stage 5 100 ns MD follows on top-10 hits per target. Results expected within 48 hours.
Why this matters
The 2026 congress made one thing clear: the "splicing-only" era is over. Combining SMN restoration with NMJ stabilisation is the next therapeutic frontier. Small-molecule MuSK/DOK7 modulators are an untouched space — ARGX-119 is a biologic, and no oral agonist exists. Even a weak hit from our campaign would be a publishable lead.
Data reproducibility: all five target entries live on sma-research.info/targets and all campaign outputs land in github.com/Bryzant-Labs/sma-research as they arrive.