In vitroeffects of S-Licarbazepine as a potential precision therapy onSCN8Avariants causing neuropsychiatric disorders

Abstract

Background and Purpose: Among genetic epilepsies, variants in sodium channel coding genes constitute a major subgroup. Variants in SCN8A, the coding gene for NaV1.6 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 NaV1.6 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 NaV1.6 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.

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

“…Although intuitive personalized therapeutic regimens tailored to diseasecausing pathophysiological mechanisms may offer the specificity required to overcome intractability, for example, by using an enhancer for voltage-gated potassium channels (11), they are currently not available in clinical standard care. Nevertheless, by following this precision medicine approach, sodium channel blockers (SCBs) seem to constitute a promising alternative providing a biophysical rationale by "narrowing" the otherwise broadened shape of APs (12) through enhancement of the inactivated state (13). In addition, some SCBs show substancespecific and distinct mechanisms, which could contribute to functional compensation of variant channels.…”

Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders

“…There have been first in silico approaches for a specific, causative treatment for KCNA1-related disorders with new substances (32) and different SCBs using a targeted "drug repurposing" approach (33). The biophysical ratio of a broadened shape of the action potential (AP) due to a reduced function of voltage-gated potassium tetramers, such as K V 1.1 subunits, and a consequently affected repolarization phase (34) seems plausible, given the fact that SCBs could "correct" this broadened AP by very welldescribed effects, such as enhancing the inactivated state (35,36), blocking the persistent sodium current [e.g., riluzole (37)], and reducing repetitive firing (38). Nevertheless, further studies in heterologous expression systems and neurons are necessary to enable individualized treatment.…”