{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T18:43:04Z","timestamp":1776883384862,"version":"3.51.2"},"reference-count":84,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"846","funder":[{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["40103996"],"award-info":[{"award-number":["40103996"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:p>\n                    The 1717-1G&gt;A is a prevalent splicing mutation causing cystic fibrosis (CF) for which no pharmacological treatments have been approved. This mutation disrupts a canonical 3\u2032 AG splice acceptor site in the\n                    <jats:italic toggle=\"yes\">cystic fibrosis transmembrane conductance regulator<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">CFTR<\/jats:italic>\n                    ) gene, leading to severe RNA missplicing, which prevents the correct synthesis of the encoded protein. In this study, we developed an adenine base editing (ABE) strategy to efficiently correct the 1717-1G&gt;A mutation. By using the ABE9 base editor with the protospacer adjacent motif\u2013relaxed\n                    <jats:italic toggle=\"yes\">Streptococcus pyogenes<\/jats:italic>\n                    clustered regularly interspaced short palindromic repeats (CRISPR)\u2013CRISPR-associated protein 9 (Cas9) variant SpRY, we obtained up to 30% editing with limited bystander effects in a human embryonic kidney (HEK) 293\u2013based cellular model. Through systematic optimizations of the ABE system, delivered by electroporation of base editor messenger RNA (mRNA) and single guide RNA (sgRNA), we demonstrated genetic repair of the 1717-1G&gt;A mutation in airway epithelial cells and intestinal organoids derived from people with CF. Functional analysis was performed by measuring short-circuit current in air-liquid interface (ALI) culture and by assessing forskolin-induced swelling (FIS) in intestinal organoids, which revealed restoration of CFTR channel activity. These results highlight SpRY-ABE9 as a potential genome editing strategy to permanently correct the\n                    <jats:italic toggle=\"yes\">CFTR<\/jats:italic>\n                    1717-1G&gt;A mutation and restore CFTR function.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adw8886","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:58:42Z","timestamp":1776880722000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Functional correction of the untreatable\n                    <i>CFTR<\/i>\n                    1717-1G&gt;A mutation through mRNA- and sgRNA-optimized base editing"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3681-3110","authenticated-orcid":true,"given":"Alessandro","family":"Umbach","sequence":"first","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8186-5539","authenticated-orcid":true,"given":"Annalisa","family":"Santini","sequence":"additional","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-3180","authenticated-orcid":true,"given":"Mattijs","family":"Bulcaen","sequence":"additional","affiliation":[{"name":"Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, B-3000 Leuven, Belgium."},{"name":"BREATHE, Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9301-8095","authenticated-orcid":true,"given":"Daniela","family":"Guidone","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Naples, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7770-5688","authenticated-orcid":true,"given":"Giulia","family":"Maule","sequence":"additional","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-6906","authenticated-orcid":true,"given":"Daniele","family":"Arosio","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, CNR, Via alla Cascata 56\/C, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8152-757X","authenticated-orcid":true,"given":"Irene","family":"Carrozzo","sequence":"additional","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2045-5435","authenticated-orcid":true,"given":"Matteo","family":"Ciciani","sequence":"additional","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9314-6976","authenticated-orcid":true,"given":"Enrica","family":"Brugnara","sequence":"additional","affiliation":[{"name":"Department CIBIO, Laboratory of Advanced Genome Editing Technologies, University of Trento, 38123 Trento, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anabela","family":"Ramalho","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8686-3461","authenticated-orcid":true,"given":"Luis J. 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