Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome

Abstract

Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy typically caused by loss-of-function de novo mutations in the SCN1A gene which encodes the voltage-gated sodium channel isoform Na_V1.1. Decreased Na_V1.1 expression results in impaired excitability of inhibitory interneurons and seizure onset. To date, there are no clinically available treatments for DS that directly address the core mechanism of disease; reduced Na_V1.1 expression levels in interneurons. Recently, Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A by the antisense oligonucleotide (ASO) STK-001, was shown to increase Scn1a mRNA levels, increase Na_V1.1 protein expression, reduce seizures, and improve survival in the Scn1a^+/- mouse model of DS. However, it remains unknown whether STK-001 treatment rescues the reduced intrinsic excitability of parvalbumin-positive (PV) inhibitory interneurons associated with DS. In this study, we demonstrate that STK-001 treatment reduces seizures, prolongs survival, and rescues PV interneuron excitability in Scn1a^+/- mice to levels observed in WT littermates. Together, these results support the notion that TANGO-mediated augmentation of Na_V1.1 levels directly targets and rescues one of the core disease mechanisms of DS.

Keywords: Antisense oligonucleotide (ASO); Epilepsy; Parvalbumin-positive (PV) inhibitory interneuron; STK-001; Voltage-gated sodium channel.