Personalized Antisense Therapy Shows Promise in Treating Rare Genetic Epilepsy in Two Patients

Two parallel single-patient studies evaluated individualized allele-selective antisense oligonucleotides in two boys aged 9 and 14 with SCN2A-related developmental epileptic encephalopathy. Patient 1 had an estimated 26% reduction in seizure counts, although the treatment effect was not statistically significant, while Patient 2 had an estimated 90% reduction and reached an average of zero daily seizures after 14 months. Both patients showed improvements across several neurodevelopmental measures, and Patient 2 achieved independent gait at age 15. The treatments were well tolerated with no ASO-related serious adverse events, but the researchers said continued long-term follow-up is needed to confirm the preliminary findings.

Antisense therapy for SCN2A epilepsy

• ▪A nonallele-selective antisense oligonucleotide reduced seizures in a premature infant with early-onset SCN2A-related disorder.
• ▪An SCN2A gapmer antisense oligonucleotide downregulated mutant transcripts, reduced seizures, and extended lifespan in an SCN2A gain-of-function mouse epilepsy model.
• ▪Antisense oligonucleotides have emerged as effective disease-modifying therapies for neurological disorders, including spinal muscular atrophy and amyotrophic lateral sclerosis.

SCN2A variants in DEE11

• ▪Developmental and epileptic encephalopathy 11 is a severe neurodevelopmental disorder caused by gain-of-function and mixed-function variants in the SCN2A gene.
• ▪Loss-of-function variants in the SCN2A gene are typically associated with autism spectrum disorder and intellectual disability with or without epilepsy.

Patient seizure reduction outcomes

• ▪Patient 1, a 9-year-old male with an SCN2A gain-of-function variant, experienced a reduction in daily average seizures from 2.2 pretreatment to 1.3–1.9 in the final 9 months of antisense oligonucleotide treatment.
• ▪Patient 2, a 14-year-old male with a mixed gain-of-function and loss-of-function SCN2A variant, achieved a 90% estimated reduction in daily seizures, reaching 0 daily average seizures after 14 months of treatment.
• ▪Patient 1 experienced an increase in seizure-free days from 57.8% before treatment to 66.5% after treatment; his estimated 26% reduction in seizure counts was not statistically significant.
• ▪Neither Patient 1 nor Patient 2 experienced seizure-related emergency room visits or hospital admissions after initiating antisense oligonucleotide therapy.

Neurodevelopmental skill improvements

• ▪Patient 1 and Patient 2 both demonstrated clinically meaningful improvements on the Observer-Reported Communication Ability measure.
• ▪Patient 1 showed improvements in Growth Scale Values across all subscales on the Bayley Scales of Infant and Toddler Development, Fourth Edition.
• ▪Patient 2 experienced a reduction in ataxia and achieved the developmental milestone of independent gait at 15 years of age.

Allele-selective ASO design strategy

• ▪Allele-selective antisense oligonucleotides are designed for individual patients because the design strategy is highly specific to the sequence of each haplotype.
• ▪Allele-selective gapmer antisense oligonucleotides use single-nucleotide polymorphisms to distinguish mutant from reference haplotypes, reducing target RNA with minimal effect on the healthy copy.

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