Selective modulation of Na V channel gating counteracts aberrant hyperexcitability and rescues motor function and survival in a model of spinal muscular atrophy

Background and Purpose Spinal muscular atrophy (SMA) is a motor neuron disease caused by SMN1 gene loss, leading to reduced survival motor neuron (SMN) protein and progressive motor neuron degeneration. Although SMN‐restoring therapies improve outcomes, residual disease burden and non‐curative efficacy underscore the need for complementary treatments. Neuronal hyperexcitability, driven by voltage‐gated sodium (Na V ) channels, has emerged as a key pathogenic mechanism in SMA and a potential therapeutic target. Experimental Approach We evaluated the therapeutic effects of ProTx‐III, a venom peptide selectively modulating Na V gating, ziconotide, a venom peptide selectively blocking N‐type calcium channel, and riluzole, an approved anti‐excitability drug, in a zebrafish smn1 −/− SMA model. Behavioural and survival assays assessed in vivo efficacy, and electrophysiological analyses of Na V channel subtypes characterised gating modulation, and state‐ and use‐dependent inhibition. Key Results Pharmacological Na V modulation significantly improved locomotor performance and extended lifespan in smn1 −/− zebrafish, with superior effects observed for ProTx‐III, compared to riluzole. In contrast, N‐type calcium channel inhibition by ziconotide yielded limited benefit. ProTx‐III produced balanced gating shifts across a broad voltage range, whereas riluzole preferentially stabilised Na V channels in the inactivated state. Both compounds exhibited use‐dependent inhibition, increasing affinity for Na V 1.2 or Na V 1.6 during high‐frequency firing. Conclusions and Implications Selective Na V gating modulation significantly preserved motor function and prolonged survival in a zebrafish SMA model. These findings establish Na V channels as a mechanistically defined, SMN‐independent, pharmacological target, supporting the potential of selective modulators such as ProTx‐III as an adjuvant in combined therapies for SMA and other motor neuron diseases.