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Rackham School of Graduate Studies, University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009712","name":"Dravet Syndrome Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009712","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS34509"],"award-info":[{"award-number":["R01 NS34509"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      De novo mutations of the voltage\u2010gated sodium channel gene\n                      <jats:italic>SCN8A<\/jats:italic>\n                      cause developmental and epileptic encephalopathy (DEE). Most pathogenic variants result in gain\u2010of\u2010function changes in activity of the sodium channel Na\n                      <jats:sub>v<\/jats:sub>\n                      1.6, poorly controlled seizures, and significant comorbidities. In previous work, an antisense oligonucleotide (ASO) reduced\n                      <jats:italic>Scn8a<\/jats:italic>\n                      transcripts and increased lifespan after neonatal administration to a mouse model. Here, we tested long\u2010term ASO treatment initiated after seizure onset, as required for clinical application.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ASO treatment was initiated after observation of a convulsive seizure and repeated at 4 to 6\u2009week intervals for 1 year. We also tested the long\u2010term efficacy of an AAV10\u2010short hairpin RNA (shRNA) virus administered on P1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Repeated treatment with the\n                      <jats:italic>Scn8a<\/jats:italic>\n                      ASO initiated after seizure onset provided long\u2010term survival and reduced seizure frequency during a 12\u2009month observation period. A single treatment with viral shRNA was also protective during 12\u2009months of observation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Downregulation of\n                      <jats:italic>Scn8a<\/jats:italic>\n                      expression that is initiated after the onset of seizures is effective for long\u2010term treatment in a model of\n                      <jats:italic>SCN8A<\/jats:italic>\n                      \u2010DEE. Repeated ASO administration or a single dose of viral shRNA prevented seizures and extended survival through 12\u2009months of observation. ANN NEUROL 2024;95:754\u2013759\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26861","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T14:12:42Z","timestamp":1702995162000},"page":"754-759","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Long\u2010Term Downregulation of the Sodium Channel Gene\n                    <i>Scn8a<\/i>\n                    Is Therapeutic in Mouse Models of\n                    <scp>\n                      <i>SCN8A<\/i>\n                    <\/scp>\n                    Epilepsy"],"prefix":"10.1002","volume":"95","author":[{"given":"Sophie F.","family":"Hill*","sequence":"first","affiliation":[{"name":"Neuroscience Graduate Program University of Michigan  Ann Arbor MI United\u00a0States"},{"name":"Department of Human Genetics University of Michigan  Ann Arbor 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H.","family":"Meisler","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program University of Michigan  Ann Arbor MI United\u00a0States"},{"name":"Department of Human Genetics University of Michigan  Ann Arbor MI"},{"name":"Department of Neurology University of Michigan  Ann Arbor 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