{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:50:45Z","timestamp":1790214645503,"version":"4.1.0"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS055925"],"award-info":[{"award-number":["R01 NS055925"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03 NS136717"],"award-info":[{"award-number":["R03 NS136717"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Iowa State University Library"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nusinersen, an antisense oligonucleotide (ASO) encompassing a phosphorothioate backbone and 2\u2032-O-methoxyethyl (MOE) modifications, is commonly used for the treatment of spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. Nusinersen acts through prevention of skipping of exon 7 of Survival Motor Neuron 2 (SMN2) by sequestering Intronic Splicing Silencer N1 (ISS-N1), located within SMN2 intron 7. Here, we report transcriptome-wide perturbations triggered by ISS-N1-targeting ASOs incorporating diverse modifications, including F18MOE, an 18mer ASO with identical sequence and chemical composition to that of nusinersen. Among cellular processes most impacted by F18MOE were cell cycle, cell growth, cell signaling, and maintenance of the cytoskeleton, chromosomes, and organelles. We demonstrate sequence-dependent and MOE modification-specific off-target effects of F18MOE on transcription and splicing. Owing to unique tolerance for mismatch base pairing with exonic targets, F18MOE triggered skipping of multiple exons, supporting the unexpected role of ISS-N1-like sequences as exonic splicing enhancers. We show that shortening of an ASO suppresses its effect on off-target splicing. Further, we demonstrate using ASOs of mixed chemistry that different MOE-modified regions drive the effect of F18MOE on off-target splicing of different exons. Our findings are instructive in designing future ASO-based therapies and for uncovering novel splicing cis-elements.<\/jats:p>","DOI":"10.1093\/narmme\/ugag002","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:29:24Z","timestamp":1767702564000},"source":"Crossref","is-referenced-by-count":3,"title":["A therapeutic antisense oligonucleotide encompassing 2\u2032-\n                    <i>O<\/i>\n                    -methoxyethyl modification triggers unique perturbation of the transcriptome"],"prefix":"10.1093","volume":"3","author":[{"given":"Eric W","family":"Ottesen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University , Ames, IA 50011,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wren A","family":"Murzyn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University , Ames, IA 50011,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L","family":"Kaas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University , Ames, IA 50011,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keaton J","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University , Ames, IA 50011,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University , Ames, IA 50011,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5399-2662","authenticated-orcid":false,"given":"Ravindra\u00a0N","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa 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