Rewriting SCN1A: Genome Editing for Genetic Epilepsies

Abstract

Prime editing of a pathogenic Scn1a allele ameliorates seizure phenotypes in a GEFS(+) mouse model Kissling L, Pietrafesa F, Ranucci M, Bock D, Mathis N, Kulcsar PI, Ioannidi E, Schmidheini L, Talas A, Villiger E, Wildner H, Zhao X, Kompotis K, Zeilhofer HU, Schwank G. Sci Transl Med. 2026;18(849):eadz2557. Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic disorder predominantly linked to autosomal-dominant, loss-of-function mutations in the sodium voltage-gated channel α subunit 1 (SCN1A) gene, which encodes the α subunit of the neuronal voltage-gated sodium ion channel type 1 (NaV1.1). Reduced NaV1.1 function in γ-aminobutyric acid (GABA)-ergic interneurons impairs inhibitory signaling and leads to neuronal hyperexcitability. Clinically, GEFS+ is characterized by a spectrum of seizure types, often beginning with febrile seizures in early childhood and progressing to generalized tonic-clonic seizures later in life. Here, we used prime editing to correct the pathogenic SCN1A-K1270 T mutation in the Scn1aKT/+ mouse model of GEFS+. Adeno-associated viral (AAV) vectors were used to deliver an intein-split prime editor under the control of a neuron-specific promoter into the cerebral ventricles of neonatal mice. This enabled efficient in vivo editing, achieving 34.7 ± 14.5% correction of the mutant allele in cortical bulk DNA, 81.2 ± 5.9% correction of mRNA, and improved multiple disease-relevant phenotypes. Survival increased from 80% in control-treated animals to 100% in treated mice, cortical inhibitory neuron transmission was improved (frequencies of inhibitory postsynaptic currents were increased from 0.32 to 1.32 hertz), and the frequency of induced febrile seizures decreased from 78.6% to 13.3%, approaching the frequency seen in wild-type mice (8%). These findings suggest the therapeutic potential of prime editing for the treatment of patients with SCN1A-associated GEFS+. In vivo adenine base editing ameliorates Dravet syndrome phenotypes in a mouse model Nelson AT, Hill SF, Simon M, Clatot J, Sakai HA, Xie J, Sousa AA, An M, Gao G, Lutz CM, Goldberg EM, Liu DR. Sci Transl Med. 2026;18(849):eadx5999. Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by drug-resistant epilepsy, temperature-sensitive seizures, cognitive impairment, and a high incidence of sudden unexpected death in epilepsy (SUDEP). DS is caused by loss-of-function variants in SCN1A, which encodes the α subunit of the voltage-gated sodium channel (Nav1.1). Current approved treatments manage symptoms of DS but do not correct the root cause of the disease. Here, we describe the use of an adenine base editor (ABE) to directly correct SCN1AR613X, a recurrent variant found in patients with DS. We identified ABE strategies to efficiently correct R613X in engineered homozygous SCN1AR613X human embryonic kidney 293 T and mouse Neuro-2a cells (72 and 92% correction efficiencies, respectively). We then used a dual-adeno-associated virus serotype 9 (AAV9) approach to deliver an optimized ABE system to Scn1aR613X/+ mice, which recapitulate several key DS pathologies. AAV9-ABE treatment of Scn1aR613X/+ neonates resulted in efficient DNA and mRNA editing (59 and 97%, respectively, in bulk neocortices), restoring parvalbumin-expressing inhibitory neuron excitability and sodium current to wild-type levels. This ameliorated both spontaneous and temperature-induced seizures and led to a 3.3-fold improvement in 45-day survival over vehicle-treated mice (ABE treated, 90%; and vehicle treated, 27%). Last, ABE treatment in 12-day-old mice resulted in a 3.0-fold improvement in 60-day survival over vehicle-treated mice (ABE treated, 82%; and vehicle treated, 27%). In conclusion, these data validate a strategy to correct SCN1A variants with ABE and highlight the potential of precision genome editing treatments for the treatment of DS and possibly other neurodevelopmental disorders.