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Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy
Olivia Kim-McManus1,2, Laurence Mignon3, Julie Douville3
1Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. okimmcmanus@health.ucsd.edu.
Nature Medicine
|July 21, 2026
Summary
Antisense oligonucleotides (ASOs) targeting SCN2A variants show promise in treating developmental and epileptic encephalopathies (DEEs). Two patients experienced reduced seizures and improved neurodevelopment, with ASOs demonstrating good tolerability.
Area of Science:
- Genetics and Neurology
- Molecular Medicine
- Pharmacogenomics
Background:
- SCN2A variants are a leading genetic cause of developmental and epileptic encephalopathies (DEEs), often involving gain-of-function mutations.
- These mutations can lead to severe, early-onset seizures and significant neurodevelopmental challenges.
Purpose of the Study:
- To evaluate the safety and efficacy of individualized, allele-selective antisense oligonucleotides (ASOs) in two pediatric patients with SCN2A-related DEE.
- To assess the impact of ASOs on seizure frequency, neurodevelopmental outcomes, and overall clinical phenotype.
Main Methods:
- Two parallel n=1 clinical studies were conducted in boys aged 9 and 14 with SCN2A-related DEE.
- Customized ASOs were designed to target heterozygous intronic SNPs, reducing mutant SCN2A transcript while preserving the wild-type allele.
- Primary endpoints included seizure frequency and neurodevelopmental assessments; secondary endpoints were individualized to each patient's specific symptoms.
Main Results:
- Patients showed significant reductions in seizure frequency (26% and 90%) and decreased reliance on concomitant anti-seizure medications.
- Improvements in neurodevelopmental skills, including motor function, were observed in both patients.
- The ASOs were well-tolerated, with no reported serious adverse events related to the treatment.
Conclusions:
- Individualized ASO therapy demonstrates preliminary safety and efficacy for SCN2A-related DEE, offering a potential disease-modifying approach.
- The study identifies a pathway for developing ASO treatments for SCN2A-RD and other monogenic disorders.
- Further long-term follow-up is necessary to confirm the disease-modifying potential and expand treatment to a larger patient cohort.
