{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:35:12Z","timestamp":1790501712493,"version":"4.1.0"},"reference-count":87,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001951","name":"Angelman Syndrome Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001951","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NICHD","award":["R01HD093771"],"award-info":[{"award-number":["R01HD093771"]}]},{"DOI":"10.13039\/100000025","name":"NIMH","doi-asserted-by":"crossref","award":["R01MH120229"],"award-info":[{"award-number":["R01MH120229"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01NS114086"],"award-info":[{"award-number":["R01NS114086"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["T32HD040127"],"award-info":[{"award-number":["T32HD040127"]}]},{"name":"NIH-NINDS","award":["P30 NS045892"],"award-info":[{"award-number":["P30 NS045892"]}]},{"name":"NIH_NICHD","award":["U54 HD079124"],"award-info":[{"award-number":["U54 HD079124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,22]]},"abstract":"<jats:p>\n                    Loss of the maternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short\/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.144712","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T14:01:06Z","timestamp":1634824866000},"source":"Crossref","is-referenced-by-count":47,"title":["Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice"],"prefix":"10.1172","volume":"6","author":[{"given":"Matthew C.","family":"Judson","sequence":"first","affiliation":[{"name":"Neuroscience Center,"},{"name":"Department of Cell Biology and Physiology,"},{"name":"Carolina Institute for Developmental Disabilities,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Shyng","sequence":"additional","affiliation":[{"name":"Carolina Institute for Developmental Disabilities,"},{"name":"Gene Therapy Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3906-1663","authenticated-orcid":true,"given":"Jeremy M.","family":"Simon","sequence":"additional","affiliation":[{"name":"Neuroscience Center,"},{"name":"Carolina Institute for Developmental Disabilities,"},{"name":"Department of Genetics, University of North Carolina (UNC), Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney R.","family":"Davis","sequence":"additional","affiliation":[{"name":"Neuroscience Center,"},{"name":"Department of Cell Biology and Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5730-7666","authenticated-orcid":true,"given":"A. 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