Adeno-associated virus-mediated restoration of NaV1.1 in targeted brain regions ameliorates epilepsy in symptomatic Dravet syndrome mice.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy primarily caused by haploinsufficiency of the SCN1A gene, which encodes the alpha subunit of NaV1.1 voltage-gated sodium channel. The disease manifests with febrile and spontaneous seizures, developmental delay, cognitive impairment, and increased risk of sudden unexpected death in epilepsy. Most preclinical therapeutic strategies aim to enhance endogenous Scn1a gene expression or deliver a functional copy via perinatal interventions. Although promising, these approaches face challenges in achieving efficient brain-wide delivery, targeting all interested brain areas.

METHODS: In this study, we used a conditional DS reversible mouse model (Scn1aStop/+) to assess the therapeutic potential of postsymptomatic restoration (postnatal day 30) of NaV1.1 physiological levels in all neuronal populations but restricted to minimal brain regions.

RESULTS: We found that hippocampal correction alone reduces seizure susceptibility, whereas simultaneous restoration in the hippocampus, thalamus, and overlying somatosensory and visual cortex was associated with a trend toward further reduction in seizure burden and improved survival.

SIGNIFICANCE: These findings indicate that hippocampal restoration accounts for a substantial component of the therapeutic benefit, and broader network correction may confer additional advantages.