Abstract Background and Purpose Among genetic epilepsies, variants in sodium channel coding genes constitute a major subgroup. Variants in SCN8A , the coding gene for Na V 1.6 channels, are characterized by a variety of symptoms including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, and others such as autistic features, ataxia or dystonia. Standard anticonvulsant treatment has only limited impact on the course of disease. Experimental Approach Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome intractability. Toward this aim, we investigated in vitro in neuroblastoma cells the effects of S-Licarbazepine, a third-generation dibenzazepine and enhancer of slow inactivation of voltage gated sodium channels, on three gain-of-function Na V 1.6 variants linked to representative phenotypes of mild epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results S-Licarbazepine strongly enhances the slow and - less pronounced – the fast inactivation of Na V 1.6 wildtype channels. It acts similarly on all tested variants and irrespective of their particular biophysical dysfunction mechanism. Beyond that S-Licarbazepine has variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D, M1760I) and a trend to reduce the enhanced persistent Na + current by A1622D variant channels. Conclusion and Implications These data bring out that S-Licarbazepine not only owns substance-specific effects, but also holds variant-specific effects, which can variably contribute to functional compensation of distinct channel-specific biophysical properties and thereby highlighting the role of personalized approaches, which likely will be key to improved and successful treatment not only of SCN8A -related disease. Bullet points What is already known? S-Lic strongly modulates slow and - to a less extend - fast inactivation of wild-type Na V 1.6 channels. What this study adds? Differential modulatory effects of S-Lic extend to Na V 1.6 A1622D, M1760I and G1475R variant channels irrespective of their leading biophysical mode of gain-of-function and variably contribute to variant-specific functional compensation of their altered biophysical properties. Clinical significance: These data suggest therapeutic potential of S-Lic for SCN8A neuropsychiatric disorders and highlight the role of personalized approaches aimed at increasingly precise correction of underlying pathophysiological mechanisms.

In vitro effects of S-Licarbazepine as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders