Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.

SCN8A encodes the voltage-gated sodium channel Nav1.6, which plays a key role in facilitating neuronal excitability. Mutations in SCN8A, particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, movement disorders, and sudden unexpected death in epilepsy (SUDEP). The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments, including antiseizure medications, are often ineffective for patients with SCN8A DEE, highlighting the need for targeted therapies. We employed base editing to correct the R1872W SCN8A variant. An adenine base editor and guide RNA (SCN8A-ABE) were packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A-ABE significantly increased survival of mice expressing R1872W and either reduced seizure incidence and severity or eliminated seizure occurrence. Electrophysiological recordings revealed a rescue of seizure-associated neuronal hyperexcitability and suppression of the pathogenic persistent sodium current (INaP) in treated mice. Comorbidities, including diminished mobility and anxiety-like behaviors, were improved by SCN8A-ABE. These effects were achieved by a 32% absolute reduction in mutant transcripts, accompanied by conversion to SCN8A WT transcripts. Our findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEEs by addressing the underlying genetic cause.