# From Symptomatic Therapies to Disease-Modifying Approaches for Neuronal Sodium Channel Disorders

## TL;DR

This paper reviews new treatments for neurological disorders caused by sodium channel gene variants, moving from symptom-based to targeted therapies.

## Contribution

The paper highlights the transition from symptomatic to precision therapies for sodium channel disorders.

## Key findings

- Current treatments for sodium channel disorders are largely ineffective and symptomatic.
- Emerging therapies like antisense oligonucleotides and gene therapy show promise in preclinical and early clinical studies.
- Pharmacological agents like fenfluramine and cannabidiol are effective for specific sodium channel-related disorders.

## Abstract

Variants in neuronal sodium channel genes are responsible for a spectrum of neurological disorders, including developmental and epileptic encephalopathies (DEEs), with considerable genetic and phenotypic heterogeneity and drug resistance. Gene variants can produce loss-, gain-, or mixed-function effects, resulting in complex genotype-phenotype correlations. Current treatments rely mainly on symptomatic polytherapy with antiseizure medications, with sodium channel blockers contraindicated in loss-of-function cases but beneficial in gain-of-function forms. Existing therapies often provide limited benefit or even no seizure control at all and fail to address developmental impairments, highlighting the need for novel approaches. Emerging strategies include antisense oligonucleotides, gene therapy, and selective small-molecule modulators, which have shown antiseizure potential in preclinical models and in initial clinical studies by modulating SCN gene expression and function. Additionally, pharmacological agents such as fenfluramine, stiripentol, and cannabidiol, although not acting directly on sodium channels, represent recognized therapeutic options for SCN1A-related Dravet syndrome. This review summarizes recent advances in approved and investigational treatments for sodium channel-related neurological disorders, highlighting the transition from symptomatic to precision therapies.