At the forefront of gene-based therapies in Dravet syndrome

Dravet syndrome (DS), a catastrophic developmental and epileptic encephalopathy primarily caused by SCN1A haploinsufficiency, remains largely refractory to current antiseizure medications. In recent years, gene-targeted therapies, including antisense oligonucleotides (ASOs)-and viral-based therapies, have emerged as promising disease-modifying strategies.

Preclinical in vitro and in vivo models demonstrated that ASO-mediated modulation of SCN1A can restore transcript and protein levels, normalize interneuron excitability, and extend survival. Key advances include the discovery of deep-intronic 'poison' exons expanding actionable ASO targets and the demonstration of long-term functional rescue after early-life administration. Complementary strategies, such as SCN8A modulation, SCN1A viral delivery, and tau suppression, further broadened therapeutic options. Clinically, the ASO STK-001 trial showed favorable safety, pharmacodynamic activity, and durable seizure reduction in Phase 1/2a and open-label extension trials, alongside improvements in adaptive behavior and cognition.

ASO-based modulation of SCN1A represents a pivotal advance in DS therapy, translating robust preclinical efficacy into early clinical benefit. Optimization of dosing regimens, durability, and combinatorial approaches targeting parallel molecular pathways will be critical to realize precision gene therapy for DS. Viral gene therapy approaches constitute a promising therapeutic platform, but comprehensive validation will be essential to ascertain their immunogenic safety and demonstrate clinical efficacy.