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As clinical sequencing technologies continue to advance, the ability to identify patients with rare disease harbouring pathogenic genetic variants amenable to this therapeutic strategy will probably improve. Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs. We describe protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a patient with Duchenne muscular dystrophy (DMD) with a structural deletion in the gene encoding dystrophin (<jats:italic>DMD<\/jats:italic>) that is amenable to treatment with existing ASO therapeutics. Furthermore, we designed novel patient-specific ASOs for two additional patients with DMD (siblings) with a deep intronic variant in the <jats:italic>DMD<\/jats:italic> gene that gives rise to a novel splice acceptor site, incorporation of a cryptic exon and premature transcript termination. We showed that treatment of patient-derived cardiac organoids with patient-specific ASOs results in restoration of DMD expression and reversal of disease-associated phenotypes. The approach outlined here provides the foundation for an expedited path towards the design and preclinical evaluation of personalized ASO therapeutics for a broad range of rare diseases.<\/jats:p>","DOI":"10.1038\/s41586-024-08462-1","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T16:05:21Z","timestamp":1737561921000},"page":"237-243","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Rapid and scalable personalized ASO screening in patient-derived organoids"],"prefix":"10.1038","volume":"638","author":[{"given":"John C.","family":"Means","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7879-3467","authenticated-orcid":false,"given":"Anabel L.","family":"Martinez-Bengochea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Louiselle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqelyn M.","family":"Nemechek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9964-5698","authenticated-orcid":false,"given":"John M.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8864-7073","authenticated-orcid":false,"given":"Emily G.","family":"Farrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-5021","authenticated-orcid":false,"given":"Tomi","family":"Pastinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6237-445X","authenticated-orcid":false,"given":"Scott T.","family":"Younger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"8462_CR1","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1056\/NEJMoa1813279","volume":"381","author":"J Kim","year":"2019","unstructured":"Kim, J. et al. 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