Antisense Oligonucleotidesin Genetic Epilepsies and Developmental and Epileptic Encephalopathies: Molecular Mechanisms, Translational Evidence and Disease-Modifying Potential

In genetic developmental and epileptic encephalopathies, disability results from both the molecular defect and epileptic activity. Antiseizure medications modulate pathways involved in seizure initiation and propagation but generally do not correct the disease-causing molecular alterations that contribute to epileptic susceptibility and neurodevelopmental dysfunction. Antisense oligonucleotides (ASOs) modify the splicing of ribonucleic acid (RNA) transcripts, promote RNA degradation, or reactivate silenced alleles. This narrative review examines variant-guided mechanisms, translational evidence, clinical outcomes, and barriers to implementation. ASO programs targeting SCN1A, SCN2A, SCN8A, KCNT1, GNAO1, and UBE3A range from individualized treatments to phase 3 trials. Published uncontrolled zorevunersen studies report preliminary clinical signals in Dravet syndrome, whereas sponsor-reported results from the randomized, sham-controlled EMBRAVE Part A study suggest seizure reduction with elsunersen in SCN2A-related disease. Conversely, sponsor-reported phase 3 Aspire topline results indicate that apazunersen did not meet its primary cognitive or key secondary multidomain endpoint in Angelman syndrome. These findings are not equivalent in evidentiary strength. Intrathecal delivery, heterogeneous central nervous system (CNS) exposure, target-dosage sensitivity, and compound-specific toxicity influence the therapeutic window. Disease modification requires controlled longitudinal demonstration of meaningful outcomes beyond target engagement or seizure reduction, considering development, adaptive functioning, survival, and treatment burden.