Antisense oligonucleotides increase <i>Scn1a</i> expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome.

Abstract

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the <i>SCN1A</i> gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit Na_V1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive <i>Scn1a</i> transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-<i>Scn1a</i> ^+/- × C57BL/6J mouse model of DS. Increased expression of productive <i>Scn1a</i> transcript and Na_V1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.