| First Author | Kissling L | Year | 2026 |
| Journal | Sci Transl Med | Volume | 18 |
| Issue | 849 | Pages | eadz2557 |
| PubMed ID | 42127217 | Mgi Jnum | J:386110 |
| Mgi Id | MGI:8346076 | Doi | 10.1126/scitranslmed.adz2557 |
| Citation | Kissling L, et al. (2026) Prime editing of a pathogenic Scn1a allele ameliorates seizure phenotypes in a GEFS(+) mouse model. Sci Transl Med 18(849):eadz2557 |
| abstractText | 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 alpha subunit 1 (SCN1A) gene, which encodes the alpha subunit of the neuronal voltage-gated sodium ion channel type 1 (Na(V)1.1). Reduced Na(V)1.1 function in gamma-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-K1270T mutation in the Scn1a(KT/+) 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(+). |
