{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:34:56Z","timestamp":1793936096551,"version":"4.8.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["CLIN2-15085 (PI: OKM)"],"award-info":[{"award-number":["CLIN2-15085 (PI: OKM)"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>SCN2A<\/jats:italic>\n                    variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1\u20132% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with\n                    <jats:italic>SCN2A<\/jats:italic>\n                    -related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant\n                    <jats:italic>SCN2A<\/jats:italic>\n                    transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient\u2019s phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with\n                    <jats:italic>SCN2A<\/jats:italic>\n                    -related disorder (\n                    <jats:italic>SCN2A<\/jats:italic>\n                    -RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from\n                    <jats:italic>n<\/jats:italic>\n                    = 1 to\n                    <jats:italic>n<\/jats:italic>\n                    of more patients with\n                    <jats:italic>SCN2A<\/jats:italic>\n                    -RD and other monogenic disorders. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06314490\" ext-link-type=\"uri\">NCT06314490<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04527-y","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:02:50Z","timestamp":1784624570000},"page":"2838-2845","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4785-7795","authenticated-orcid":false,"given":"Olivia","family":"Kim-McManus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Mignon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8783-6676","authenticated-orcid":false,"given":"Julie","family":"Douville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Parisien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Frank","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janelle","family":"Celso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendall","family":"Robbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2088-4889","authenticated-orcid":false,"given":"Hoameng","family":"Ung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7180-2527","authenticated-orcid":false,"given":"Stephen F.","family":"Kingsmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Petrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4260-1520","authenticated-orcid":false,"given":"Stanley T.","family":"Crooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0889-9220","authenticated-orcid":false,"given":"Joseph G.","family":"Gleeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7099-1522","authenticated-orcid":false,"given":"Elizabeth","family":"Berry-Kravis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"4527_CR1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1111\/epi.12550","volume":"55","author":"RS Fisher","year":"2014","unstructured":"Fisher, R. 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Epilepsia 66, 776\u2013789 (2025).","journal-title":"Epilepsia"},{"key":"4527_CR4","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1016\/S1474-4422(14)70123-1","volume":"13","author":"AL George Jr.","year":"2014","unstructured":"George, A. L. Jr. Lessons learned from genetic testing for channelopathies. Lancet Neurol. 13, 1068\u20131070 (2014).","journal-title":"Lancet Neurol."},{"key":"4527_CR5","doi-asserted-by":"publisher","first-page":"S68","DOI":"10.1111\/epi.14731","volume":"60","author":"UBS Hedrich","year":"2019","unstructured":"Hedrich, U. B. S., Lauxmann, S. & Lerche, H. SCN2A channelopathies: mechanisms and models. Epilepsia 60, S68\u2013S76 (2019).","journal-title":"Epilepsia"},{"key":"4527_CR6","doi-asserted-by":"publisher","first-page":"4375","DOI":"10.1113\/JP281834","volume":"599","author":"S Ganguly","year":"2021","unstructured":"Ganguly, S., Thompson, C. H. & George, A. L. Jr. Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy. J. Physiol. 599, 4375\u20134388 (2021).","journal-title":"J. Physiol."},{"key":"4527_CR7","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1093\/brain\/awae125","volume":"147","author":"AT Berg","year":"2024","unstructured":"Berg, A. T. et al. Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain 147, 2761\u20132774 (2024).","journal-title":"Brain"},{"key":"4527_CR8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI152079","volume":"131","author":"M Li","year":"2021","unstructured":"Li, M. et al. Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model. J. Clin. Invest. 131, e152079 (2021).","journal-title":"J. Clin. 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Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder. Mol. Ther. Nucleic Acids. 36, 102432 (2024).","journal-title":"Mol. Ther. Nucleic Acids."},{"key":"4527_CR12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2317769121","volume":"121","author":"A Eltokhi","year":"2024","unstructured":"Eltokhi, A. et al. Pathogenic gating pore current conducted by autism-related mutations in the NaV1.2 brain sodium channel. Proc. Natl Acad. Sci. USA. 121, e2317769121 (2024).","journal-title":"Proc. Natl Acad. Sci. USA."},{"key":"4527_CR13","doi-asserted-by":"publisher","unstructured":"Kim-McManus, O. et al. Scaling haplospecific antisense oligonucleotides from N-of-1 to broad use in genetic disease populations by diplotyping. 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J.G.G. is a paid consultant for Ionis Pharmaceuticals and the n-Lorem Foundation. C.F.B. is an employee of Ionis Pharmaceuticals. S.P. is an employee of Praxis Precision Medicines. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}