No disease-modifying therapies exist for Dravet syndrome (DS), a severe form of epilepsy mostly caused by de novo mutations in SCN1A that result in NaV1.1 haploinsufficiency. Applying their targeted augmentation of nuclear gene output (TANGO) technology, Han et al. identify an ASO targeting a naturally occurring nonproductive alternative splicing event in SCN1A that results in nonsense-mediated decay of the wild-type transcript. The ASO increased expression of productive SCN1A mRNA and NaV1.1 protein in human cells and mouse brain. A single intracerebroventricular dose reduced seizure incidence and sudden unexpected death in epilepsy in DS mice.
Nature Reviews Drug Discovery 19, 672 (2020)