Gene therapies alleviate absence epilepsy associated with deficiency in DBA/2J mice.

Mutations in the voltage-gated sodium channel gene , which encodes the Na1.2 channel, cause severe epileptic seizures. Patients with loss-of-function (LoF) mutations, such as protein-truncating mutations, often experience later-onset and drug-resistant epilepsy, highlighting an urgent unmet clinical need for new therapies. We previously developed a gene-trap ( ) mouse model with a global Na1.2 reduction in the widely used C57BL/6N (B6) strain. Although these mice display multiple behavioral abnormalities, EEG recordings indicated only mild epileptiform discharges, possibly attributable to the seizure-resistant characteristics associated with the B6 strain. To enhance the epileptic phenotype, we derived congenic mice in the seizure-susceptible DBA/2J (D2J) strain. Notably, we found that these mice exhibit prominent spontaneous absence seizures, marked by both short and long spike-wave discharges (SWDs). Restoring Na1.2 expression in adult mice substantially reduced their SWDs, suggesting the possibility of gene replacement therapy during adulthood. RNA sequencing revealed significant alterations in gene expression in the mice, in particular a broad downregulation of voltage-gated potassium channel (K) genes, including K1.1. The reduction of K1.1 expression was further validated in human cerebral organoids with deficiency, highlighting K1.1 as a promising therapeutic target for refractory seizures associated with dysfunction. Importantly, delivery of exogenous human K1.1 expression via adeno-associated virus (AAV) in D2J mice substantially reduced absence seizures. Together, these findings underscore the influence of mouse strain on seizure severity and highlight the potential of targeted gene therapies for treating deficiency-related epilepsies.