Base Editing Rescue of Seizures and SUDEP in SCN8A Developmental Epileptic Encephalopathy

SCN8A encodes the sodium channel Na _v 1.6; mutations in SCN8A , particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, and seizure-induced death. The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments for SCN8A DEE are often ineffective, highlighting the need for targeted therapies. Here we employed base editing to correct the R1872W SCN8A variant. A modified adenine base editor ( SCN8A -ABE) was packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A -ABE significantly increased survival and reduced or eliminated seizures. Neuronal hyperexcitability and heightened sodium currents were attenuated with SCN8A -ABE treatment, and behavioral comorbidities were improved. These effects were achieved by approximately 30% conversion of mutant to wildtype SCN8A transcripts. These findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEE by addressing the underlying genetic cause.