Dravet syndrome (DS) is a severe and difficult-to-treat epileptic syndrome usually caused by a loss-of-function mutation in SCN1A, which encodes the voltage-gated sodium channel 1.1 (NaV1.1), resulting in interneuron inhibitory dysfunction. Here, Mich and colleagues developed a gene replacement therapy for DS that specifically targets these interneurons. SCN1A was split into two halves to fit within adeno-associated virus (AAV) capsids, and split intein technology was used to reconstitute the halves into the full NaV1.1 protein after translation. After adding previously developed enhancer technology to target SCN1A expression to interneurons, they tested the dual-AAV system on two mouse models of DS, showing improvements in postnatal mortality and reduction in both febrile and spontaneous seizures. These studies support further investigation of gene therapies targeting interneurons for the treatment of patients with DS. —Melissa L. Norton
