Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

Allele-selective antisense oligonucleotides targeting heterozygous intronic SNPs, reducing expression of the mutant SCN2A transcript — gain-of-function or mixed-function variants — while preserving the wild-type copy.

Two parallel n = 1 clinical studies were conducted in two boys aged 9 and 14 years with SCN2A-related developmental and epileptic encephalopathy. Allele-selective antisense oligonucleotides designed to target heterozygous intronic SNPs were used to lower expression of the mutant transcript while preserving the wild-type copy. Both patients showed reduced seizure frequency (26% and 90%), decreased use of concomitant medications and improvement in neurodevelopmental skills, with no treatment-related serious adverse events. In a separate cohort of infants diagnosed by rapid whole-genome sequencing, haplotype phasing identified 16% of patients carrying SNPs compatible with this strategy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Only two patients, but an important proof of principle: an allele-selective antisense oligonucleotide can target a gain-of-function allele without touching the wild-type copy, which was the conceptual barrier in SCN2A. The most telling figure for a laboratory is the 16% eligibility rate obtained by haplotype phasing: it turns the genomic report into a therapeutic selection step and makes retaining phase information necessary. Responses were highly heterogeneous (26% versus 90%) and follow-up short — no generalisable efficacy conclusion at this stage.

Analysis by Dr Thibaut Benquey