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

ABSTRACT 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.