Dr Lori L. Isom - Dancing to a different tune: TANGO offers a precision medicine approach to treating Dravet syndrome
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Descriptif
Dravet syndrome is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. We employed Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, non-productive splicing events to increase target gene and protein expression and ameliorate disease phenotype. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human and mouse cell lines, as well as in mouse brain. We showed that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 significantly reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a+/- x C57BL/6J mouse model of Dravet syndrome. Increased levels of productive Scn1a transcript and NaV1.1 protein were confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of Dravet syndrome.
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