Terapia genowa naprawiająca epilepsję i nadmierną aktywność mózgu w modelach niedoboru SCN2A

Pathogenic SCN2A loss-of-function (LoF) variants can cause severe, refractory epilepsy with limited treatment options. Existing Scn2a-LoF mouse models exhibit few spontaneous seizures, limiting the dynamic range needed to assess therapeutic efficacy. We therefore generated gene-trap Scn2a-deficient mice on the seizure-prone DBA/2J background. These mice experienced hundreds of spontaneous absence seizures per day, characterized by concurrent behavioral arrest and EEG spike-wave discharges (SWDs). Partial restoration of Scn2a expression reduced seizure burden. Electrophysiological analysis revealed impaired action potential waveforms yet increased repetitive firing, alongside coordinated downregulation of voltage-gated potassium channel genes, potentially contributing to hyperexcitability. Given the broad potassium channel downregulation and prior efficacy of KCNA1 gene therapy in refractory seizure models, we selected KV1.1 as a potential therapeutic target and used a drug-controllable adeno-associated virus (AAV) to express human KCNA1. We found that this intervention normalized elevated neuronal firing and reduced spontaneous seizure burden in Scn2a-deficient mice. Extending these findings to a human cell-based platform, AAV-mediated KCNA1 expression also reduced neuronal firing in human cortical organoids carrying a SCN2A-truncating variant identified in patients. Together, these findings provide proof of principle for drug-controllable KCNA1 gene therapy as a promising treatment avenue for epilepsy related to SCN2A LoF variants.