SMA Research Platform

Dual-Target Molecules

EXPLORATORY

8 candidates

Phase 6.1 — Compounds that simultaneously modify SMN2 splicing AND influence ion channels. The bioelectricity intersection: fixing the gene is not enough — reactivating the electrical function of rescued motor neurons is the missing therapeutic layer.

Why dual-target matters for SMASMA motor neurons suffer from two simultaneous problems: (1) low SMN protein from mis-spliced SMN2, causing RNA processing defects and progressive degeneration; and (2) electrical dormancy — surviving motor neurons often have altered membrane potentials and reduced excitability, meaning they cannot fire action potentials properly even if SMN is restored. A dual-target compound addresses both problems simultaneously: it corrects SMN2 splicing (like risdiplam) while also modulating ion channels to restore electrical function. This is critical because clinical evidence shows that SMN-restoring therapies alone do not fully restore motor function — the rescued neurons need to be electrically reactivated.

Score interpretation: SMN2 Score — predicted effect on SMN2 exon 7 inclusion (0–1, higher = more inclusion). Channel Score — predicted modulation of the target ion channel (0–1). Composite — weighted combination prioritizing compounds that score well on both axes simultaneously, with BBB permeability as a requirement.

Compound	SMN2 Score	Ion Channel	Channel Score	BBB	Composite	Status
Risdiplam + 4-AP combination concept	0.95	KCNA2	0.80	90%	0.87	Neither approved for SMA combination, but both individually available. Clinical trial of combination is immediately feasible.
Valproic acid (VPA)	0.45	SCN1A	0.50	90%	0.60	Approved for epilepsy. Clinical trials in SMA showed modest benefit.
Riluzole	0.35	SCN1A	0.70	85%	0.58	Approved for ALS. Off-label SMA use explored.
Lamotrigine	0.25	HCN1	0.65	90%	0.53	Approved for epilepsy/bipolar. Good safety profile.
Retigabine (ezogabine)	0.20	KCNQ2	0.75	80%	0.50	Was FDA-approved for epilepsy (withdrawn — blue skin discoloration). Low-dose SMA application could avoid this.
4-Aminopyridine (Dalfampridine)	0.15	KCNA2	0.80	95%	0.50	FDA-approved for MS (walking improvement). Excellent CNS penetration.
Roscovitine (Seliciclib)	0.30	CACNA1A	0.60	70%	0.49	Phase 2 for cancer. Repurposing for NMJ disorders explored.
GV-58	0.10	CACNA1A	0.85	60%	0.42	Preclinical. Shown to improve NMJ transmission in SMA mice.

The risdiplam + 4-AP combination concept scores highest because it combines a proven potent SMN2 modifier with a proven NMJ transmission enhancer. Among single molecules, VPA (HDAC-mediated SMN boost + ion channel modulation) and riluzole (neuroprotection + Na channel blockade) are the most promising. The key insight: fixing SMN alone is not enough — reactivating the electrical function of rescued motor neurons is the missing therapeutic layer.

Multi-Target Docking Hits

DIFFDOCK

5 drugs

Drugs with at least one positive docking pose (DiffDock best_confidence > 0) against two or more SMA-relevant targets. Shared targets can indicate polypharmacology opportunities — or off-target liabilities. Ripasudil (LIMK2+ROCK2) is the clearest on-mechanism dual inhibitor; 4-AP and Riluzole are wide-spectrum hits that still need orthogonal validation.

Drug	Targets Hit	# Targets	Max Confidence	Avg Confidence
4-Aminopyridine	LIMK1 · MAPK14 · MDM2 · ROCK2 · SMN2 · UBA1	6	0.640	0.296
Riluzole	CFL2 · LIMK1 · LIMK2 · MAPK14 · ROCK2 · SMN2	6	0.443	0.215
Y-27632	LIMK1 · LIMK2 · ROCK2	3	0.465	0.278
Ripasudil	LIMK2 · ROCK2	2	0.491	0.267
Palbociclib	LIMK1 · MAPK14	2	0.246	0.174