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<p>Dravet syndrome (DS) is a severe infantile-onset developmental and epileptic encephalopathy characterised by frequent drug-resistant seizures, cognitive and motor impairment, and an elevated risk of premature mortality, particularly from sudden unexpected death in epilepsy (SUDEP). Over 95% of cases are caused by loss-of-function pathogenic variants in <i>SCN1A,</i> the gene encoding the voltage-gated sodium channel alpha-1 subunit, Na<sub>V</sub>1.1. Despite advances in the understanding of DS pathophysiology, current treatments have primarily targeted seizure control without addressing the myriad of associated morbidities and the underlying molecular defect. Recent therapeutic developments include the approval of new antiseizure medications such as fenfluramine and pharmaceutical-grade cannabidiol, which have demonstrated efficacy and tolerability in randomised placebo-controlled trials. Investigational therapies, including selective serotonin receptor modulators and RNA-based and gene-based strategies, are expanding the treatment landscape. Antisense oligonucleotides (e.g., STK-001) aim to restore SCN1A expression, while emerging gene therapy approaches, including engineered AAV vectors (e.g., ETX101) and CRISPR-mediated transcriptional activation, seek to directly modify disease biology. Although challenges remain, such as long-term safety concerns, a broad spectrum of phenotypic severity, and efficacy and accessibility of advanced therapies, rapid progress in therapeutic research for DS offers new hope. Future directions include defining the most effective genetic therapies to improve outcomes, and ideally cure, all features of DS; optimal timing to deliver interventions as well as benefits derived from administration at later ages; ideal combinations of therapies; comparison of outcomes of targeted therapies with natural history studies and biomarker development. Together, these advances signal a paradigm shift in epilepsy management from symptomatic treatment to precision medicine for children and adults with DS.</p>

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Ameliorating Seizures in Dravet Syndrome: A Review of Newly Approved and Investigational Drugs, RNA and Gene-Based Therapies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Simona Balestrini,
  • Ingrid E. Scheffer

摘要

Dravet syndrome (DS) is a severe infantile-onset developmental and epileptic encephalopathy characterised by frequent drug-resistant seizures, cognitive and motor impairment, and an elevated risk of premature mortality, particularly from sudden unexpected death in epilepsy (SUDEP). Over 95% of cases are caused by loss-of-function pathogenic variants in SCN1A, the gene encoding the voltage-gated sodium channel alpha-1 subunit, NaV1.1. Despite advances in the understanding of DS pathophysiology, current treatments have primarily targeted seizure control without addressing the myriad of associated morbidities and the underlying molecular defect. Recent therapeutic developments include the approval of new antiseizure medications such as fenfluramine and pharmaceutical-grade cannabidiol, which have demonstrated efficacy and tolerability in randomised placebo-controlled trials. Investigational therapies, including selective serotonin receptor modulators and RNA-based and gene-based strategies, are expanding the treatment landscape. Antisense oligonucleotides (e.g., STK-001) aim to restore SCN1A expression, while emerging gene therapy approaches, including engineered AAV vectors (e.g., ETX101) and CRISPR-mediated transcriptional activation, seek to directly modify disease biology. Although challenges remain, such as long-term safety concerns, a broad spectrum of phenotypic severity, and efficacy and accessibility of advanced therapies, rapid progress in therapeutic research for DS offers new hope. Future directions include defining the most effective genetic therapies to improve outcomes, and ideally cure, all features of DS; optimal timing to deliver interventions as well as benefits derived from administration at later ages; ideal combinations of therapies; comparison of outcomes of targeted therapies with natural history studies and biomarker development. Together, these advances signal a paradigm shift in epilepsy management from symptomatic treatment to precision medicine for children and adults with DS.