Augmenting and Assaying Nav1.1 Protein Quantity for Dravet Syndrome Therapy

Dravet Syndrome (DS) is a developmental and epileptic encephalopathy predominantly caused by heterozygous loss-of-function variants in SCN1A, which encodes Nav1.1. Conserved upstream open reading frames (uORFs) in SCN1A were validated to regulate translation in reporter assays, demonstrating the therapeutic viability of increasing Nav1.1 from a wild-type allele. A human induced pluripotent stem cell (iPSC) line with endogenously HiBiT-tagged Nav1.1 showed dose-dependent Nav1.1 downregulation with gapmer antisense oligonucleotides (ASOs) and upregulation with splice-switching ASOs, validating a sensitive quantification platform for endogenous Nav1.1 translation. This iPSC line provides a timely resource for screening translational modulators and validating therapeutic strategies for SCN1A-related disorders.