Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy

Heterozygous mutations within the voltage-gated sodium channel α subunit ( ) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. We investigated mRNA expression and expression of two related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against specific antisense RNAs on expression was tested. The related antisense RNAs -dsAS (downstream antisense, RefSeq identifier: NR_110598) and -usAS (upstream AS, -AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA -usAS with mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against -dsAS was associated with a significant enhancement of mRNA expression and reduction in -dsAS transcripts. These findings support the role of -dsAS in the suppression of mRNA generation. Considering the haploinsufficiency in genetic related DS, -dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance expression in DS.