{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:29:00Z","timestamp":1790695740389,"version":"4.1.0"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR071170"],"award-info":[{"award-number":["R01AR071170"]}],"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":["R01AR062189"],"award-info":[{"award-number":["R01AR062189"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Myotonic dystrophy type 1 (DM1), the most common adult muscular dystrophy, is an autosomal dominant disorder caused by an expansion of a (CTG)n tract within the 3\u2032 untranslated region (3\u2032UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Mutant DMPK mRNAs are toxic, present in nuclear RNA foci and correlated with a plethora of RNA splicing defects. Cardinal features of DM1 are myotonia and cardiac conduction abnormalities. Using transgenic mice, we have demonstrated that expression of the mutant DMPK 3\u2032UTR is sufficient to elicit these features of DM1. Here, using these mice, we present a study of systemic treatment with an antisense oligonucleotide (ASO) (ISIS 486178) targeted to a non-CUG sequence within the 3\u2032UTR of DMPK. RNA foci and DMPK 3\u2032UTR mRNA levels were reduced in both the heart and skeletal muscles. This correlated with improvements in several splicing defects in skeletal and cardiac muscles. The treatment reduced myotonia and this correlated with increased Clcn1 expression. Furthermore, functional testing showed improvements in treadmill running. Of note, we demonstrate that the ASO treatment reversed the cardiac conduction abnormalities, and this correlated with restoration of Gja5 (connexin 40) expression in the heart. This is the first time that an ASO targeting a non-CUG sequence within the DMPK 3\u2032UTR has demonstrated benefit on the key DM1 phenotypes of myotonia and cardiac conduction defects. Our data also shows for the first time that ASOs may be a viable option for treating cardiac pathology in DM1.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa060","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T19:19:09Z","timestamp":1585682349000},"page":"1440-1453","source":"Crossref","is-referenced-by-count":37,"title":["Systemic therapy in an RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3\u2032UTR RNA"],"prefix":"10.1093","volume":"29","author":[{"given":"Ramesh S","family":"Yadava","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahua","family":"Mandal","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rigo","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals Inc., Carlsbad, CA 90210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Frank","family":"Bennett","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals Inc., Carlsbad, CA 90210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mani S","family":"Mahadevan","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"2020060307000272000_ref1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.nmd.2004.09.012","article-title":"RNA pathogenesis of the myotonic dystrophies","volume":"15","author":"Day","year":"2005","journal-title":"Neuromuscul. 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