Paradigm correction

Initial (wrong) framing: "Does 4-AP modulate SMN2 splicing or replace nusinersen?"
Answer (after MD evidence + Simon input): NO. 4-AP does not bind SMN2 (binding_contacts: [] after 18.6 ns MD). It is NOT a disease-modifying therapy.

Correct framing: 4-AP is a complementary recovery agent that works alongside SMN-restoration therapies (nusinersen, risdiplam, onasemnogene, ABE base editing). Track B of the Universal Recovery Platform, parallel to Fasudil/LIMK2 on Track A (ROCK-LIMK2-CFL2 axis).

Two mechanisms that matter for SMA

Mechanism A — Axonal excitability (validated)

• 4-AP blocks Kv1.2 → delayed axonal repolarization → prolonged action potential → improved NMJ transmission
• Our computational evidence: Kv1.2 holo MD 12.3 ns stable, energy drift 0.0025%
• DiffDock panel: Kv1.2 confidence −0.58 (best of 5 tested targets; Kv1.2 >> Kv3.1 > SARM1 > Kv7.1 >>> RIPK1)
• Clinical precedent: FDA-approved as Ampyra® for MS walking difficulty (same mechanism), safe in Lambert-Eaton

Mechanism B — Regeneration/remyelination (Simon's hypothesis, emerging literature)

• Remyelination: 4-AP increases OPC differentiation in MS models
• Schwann cell activation in peripheral nerve repair
• NMJ reinnervation enhancement after denervation
• BDNF/GDNF upregulation in treated tissue

If these effects translate to SMA, 4-AP provides structural recovery of motor neurons surviving with genetic rescue.

The Universal Recovery Platform

            SMN RESTORATION (fix the gene)
    nusinersen / risdiplam / onasemnogene / ABE
                        |
                        v
              surviving motor neurons
               /                    \
              v                      v
    Track A (ROCK-LIMK-CFL2)   Track B (excitability + regen)
     Fasudil, LIMK2 hits        4-AP / dalfampridine
     structural (actin)          functional (firing + growth)

Our unique angle: pharma competes on SMN restoration; we build the recovery platform that works downstream of ANY SMN fix.

What we claim

• ✅ 4-AP has validated Kv1.2 binding (our MD + FDA label)
• ✅ 4-AP does NOT affect SMN2 (safe to co-administer with any SMN modulator)
• ✅ 4-AP is a candidate for Simon's wet-lab testing as SMA adjunct

What we do NOT claim

• ❌ 4-AP alone cures SMA
• ❌ 4-AP replaces nusinersen/risdiplam/onasemnogene
• ❌ 4-AP regenerates motor neurons in SMA (hypothesis, unvalidated)

Proposed wet-lab experiments (for Simon)

Exp 1: 4-AP + nusinersen in Δ7-SMA mice (vehicle / nusinersen / 4-AP / combo). Endpoints: survival, rotarod, grip strength, NMJ α-bungarotoxin, motor neuron count. 1 mg/kg/day.

Exp 2: ABE + Fasudil + 4-AP triple combination (vehicle / ABE / ABE+Fasudil / ABE+Fasudil+4-AP). Endpoints: same + phalloidin actin staining.

Exp 3: Sciatic nerve crush in SMN-deficient mice ± 4-AP — direct regeneration readout.

No papers to date combine 4-AP + ABE or 4-AP + Fasudil in SMA models — this would be a novel contribution.

CC-BY-4.0. Full finding: /findings/2026-04-10/FINDING_2026-04-10_4AP_complementary_recovery.md.