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A solution for Dravet?
Mutations in SCN1A, the gene encoding for the sodium channel NaV1.1, cause Dravet syndrome (DS), a developmental epileptic encephalopathy. Current therapies can provide partial seizure management, but therapies targeting the cause of the disease are lacking. Now, Han et al. used Targeted Augmentation of Nuclear Gene Output (TANGO) technology to develop an antisense oligonucleotide (ASO) able to increase NaV1.1 expression in vitro in cultured human cells and in vivo in a mouse model of DS. In mice, intracerebral delivery of ASO prevented epilepsy-associated death and reduced seizure frequency and severity. The results suggest that this approach could be effective for treating DS.
Abstract
Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. 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 Scn1a 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-Scn1a+/− × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 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.
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