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Med."],"published-print":{"date-parts":[[2026,5,13]]},"abstract":"<jats:p>\n                    Generalized epilepsy with febrile seizures plus (GEFS\n                    <jats:sup>+<\/jats:sup>\n                    ) is an inherited epileptic disorder predominantly linked to autosomal-dominant, loss-of-function mutations in the sodium voltage-gated channel \u03b1 subunit 1 (\n                    <jats:italic toggle=\"yes\">SCN1A<\/jats:italic>\n                    ) gene, which encodes the \u03b1 subunit of the neuronal voltage-gated sodium ion channel type 1 (Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1). Reduced Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1 function in \u03b3-aminobutyric acid (GABA)\u2013ergic interneurons impairs inhibitory signaling and leads to neuronal hyperexcitability. Clinically, GEFS\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic toggle=\"yes\">SCN1A<\/jats:italic>\n                    -K1270T mutation in the\n                    <jats:italic toggle=\"yes\">Scn1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic toggle=\"yes\">KT\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    mouse model of GEFS\n                    <jats:sup>+<\/jats:sup>\n                    . 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\u00a0\u00b1\u00a014.5% correction of the mutant allele in cortical bulk DNA, 81.2\u00a0\u00b1\u00a05.9% 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\n                    <jats:italic toggle=\"yes\">SCN1A<\/jats:italic>\n                    -associated GEFS\n                    <jats:sup>+<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adz2557","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:58:22Z","timestamp":1778695102000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Prime editing of a pathogenic\n                    <i>Scn1a<\/i>\n                    allele ameliorates seizure phenotypes in a GEFS\n                    <sup>+<\/sup>\n                    mouse model"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-0695","authenticated-orcid":true,"given":"Lucas","family":"Kissling","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1458-1677","authenticated-orcid":true,"given":"Francesca","family":"Pietrafesa","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-6202","authenticated-orcid":true,"given":"Matteo","family":"Ranucci","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-0629","authenticated-orcid":true,"given":"Desir\u00e9e","family":"B\u00f6ck","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4051-8344","authenticated-orcid":true,"given":"Nicolas","family":"Mathis","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter Istv\u00e1n","family":"Kulcs\u00e1r","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, 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