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In this study, nine antisense oligonucleotides (AONs) were designed to correct pseudoexon (PE) inclusion caused by a recurrent deep-intronic variant in ABCA4 (c.769-784C&gt;T). First, the ability of AONs to skip the PE from the final ABCA4 mRNA transcript was assessed in two cellular models carrying the c.769-784C&gt;T variant: a midigene assay using HEK293T cells and patient-derived fibroblasts. Based on the splicing-correcting ability of each individual AON, the three most efficacious AONs targeting independent regions of the PE were selected for a final assessment in photoreceptor precursor cells (PPCs). The final analysis in the PPC model confirmed high efficacy of AON2, -5, and -7 in promoting PE exclusion. Among the three AONs, AON2 is chosen as the lead candidate for further optimization, hereby showcasing the high potential of AONs to correct aberrant splicing events driven by deep-intronic variants.<\/jats:p>","DOI":"10.3390\/cells11243947","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T03:27:57Z","timestamp":1670383677000},"page":"3947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Correction of the Splicing Defect Caused by a Recurrent Variant in ABCA4 (c.769-784C&gt;T) That Underlies Stargardt Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2572-7690","authenticated-orcid":false,"given":"Tomasz Z.","family":"Tomkiewicz","sequence":"first","affiliation":[{"name":"Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Nieuwenhuis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans P. M.","family":"Cremers","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5721-1560","authenticated-orcid":false,"given":"Alejandro","family":"Garanto","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Amalia Children\u2019s Hospital, Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4347-6503","authenticated-orcid":false,"given":"Rob W. J.","family":"Collin","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Newsome, D.A. (1988). Fundus flavimaculatus. Retinal Dystrophies and Degenerations, Raven Press.","DOI":"10.1097\/00003226-198903000-00015"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/ng0397-236","article-title":"A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy","volume":"15","author":"Allikmets","year":"1997","journal-title":"Nat. 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