{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:19:30Z","timestamp":1790889570044,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS055925"],"award-info":[{"award-number":["R01 NS055925"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intronic splicing silencer N1 (ISS-N1) located within Survival Motor Neuron 2 (SMN2) intron 7 is the target of a therapeutic antisense oligonucleotide (ASO), nusinersen (Spinraza), which is currently being used for the treatment of spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. The discovery of ISS-N1 as a promising therapeutic target was enabled in part by Anti-N1, a 20-mer ASO that restored SMN2 exon 7 inclusion by annealing to ISS-N1. Here, we analyzed the transcriptome of SMA patient cells treated with 100 nM of Anti-N1 for 30 h. Such concentrations are routinely used to demonstrate the efficacy of an ASO. While 100 nM of Anti-N1 substantially stimulated SMN2 exon 7 inclusion, it also caused massive perturbations in the transcriptome and triggered widespread aberrant splicing, affecting expression of essential genes associated with multiple cellular processes such as transcription, splicing, translation, cell signaling, cell cycle, macromolecular trafficking, cytoskeletal dynamics, and innate immunity. We validated our findings with quantitative and semiquantitative PCR of 39 candidate genes associated with diverse pathways. We also showed a substantial reduction in off-target effects with shorter ISS-N1-targeting ASOs. Our findings are significant for implementing better ASO design and dosing regimens of ASO-based drugs.<\/jats:p>","DOI":"10.3390\/ijms22168378","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T08:47:52Z","timestamp":1628066872000},"page":"8378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome"],"prefix":"10.3390","volume":"22","author":[{"given":"Eric William","family":"Ottesen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diou","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia Nikolaevna","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5399-2662","authenticated-orcid":false,"given":"Ravindra Narayan","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.cmet.2018.03.004","article-title":"RNA-Targeted Therapeutics","volume":"27","author":"Crooke","year":"2018","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.ymthe.2020.12.022","article-title":"Clinical Applications of Single-Stranded Oligonucleotides: Current Landscape of Approved and In-Development Therapeutics","volume":"29","author":"Scharner","year":"2021","journal-title":"Mol. 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