SCN1A mRNA

Class

antisense oligonucleotide (zorevunersen), built on Stoke's TANGO splice-modulation platform

Pathway

binds SCN1A pre-mRNA to promote productive splicing (excluding a poison exon subject to nonsense-mediated decay), upregulating NaV1.1 sodium channel protein from the non-mutant SCN1A allele to restore inhibitory interneuron function

SCN1A encodes NaV1.1, a voltage-gated sodium channel expressed largely in inhibitory (GABAergic) interneurons in the brain. These neurons rely on NaV1.1 to fire the action potentials that dampen excessive excitatory signaling elsewhere in neural circuits. In certain severe genetic epilepsies, one copy of SCN1A carries a loss-of-function mutation, and the single remaining healthy copy does not produce enough channel protein to sustain normal interneuron firing — a state called haploinsufficiency. This antisense oligonucleotide mechanism works not by blocking a target but by increasing its output: it binds the pre-messenger RNA transcribed from SCN1A and redirects how it is spliced, excluding a naturally occurring "poison exon" that would otherwise trigger degradation of the transcript before it can be translated. By favoring the productive splice form, more NaV1.1 protein is generated from the functioning allele. The underlying rationale is that restoring channel abundance toward normal levels, rather than introducing a wholly new protein, corrects the interneuron dysfunction that underlies the disease's seizures and developmental impact. This splice-modulation strategy exemplifies a broader class of approaches applicable to other haploinsufficiency disorders, where boosting expression of an intact gene copy is therapeutically sufficient.