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TS type\u20091 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    exon\u20098A, as opposed to its counterpart exon\u20098. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon\u20098A\n                    <jats:sup>2\u20136<\/jats:sup>\n                    . We reasoned that switching\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon\u20098A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon\u20098A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed\n                    <jats:sup>7<\/jats:sup>\n                    , we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    exon\u20098A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07310-6","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T12:02:00Z","timestamp":1713960120000},"page":"818-825","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Antisense oligonucleotide therapeutic approach for Timothy syndrome"],"prefix":"10.1038","volume":"628","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4009-8156","authenticated-orcid":false,"given":"Xiaoyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-2764","authenticated-orcid":false,"given":"Fikri","family":"Birey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8102-632X","authenticated-orcid":false,"given":"Min-Yin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Revah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuri Vijay","family":"Thete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7258-2463","authenticated-orcid":false,"given":"Noah","family":"Reis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Kaganovsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Onesto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriaki","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Hudacova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6685-2017","authenticated-orcid":false,"given":"Jin","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3528-4037","authenticated-orcid":false,"given":"Xiangling","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Huguenard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-3248","authenticated-orcid":false,"given":"Sergiu P.","family":"Pa\u0219ca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"key":"7310_CR1","doi-asserted-by":"publisher","first-page":"8089","DOI":"10.1073\/pnas.0502506102","volume":"102","author":"I Splawski","year":"2005","unstructured":"Splawski, I. et al. 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