{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T19:44:25Z","timestamp":1777923865393,"version":"3.51.4"},"reference-count":47,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T00:00:00Z","timestamp":1585180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T00:00:00Z","timestamp":1585180800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2020,4,1]]},"abstract":"<jats:p>\n                    Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystemic disorder characterized clinically by delayed muscle relaxation and weakness. The disease is caused by a CTG repeat expansion in the 3\u2032 untranslated region (3\u2032 UTR) of the\n                    <jats:italic toggle=\"yes\">DMPK<\/jats:italic>\n                    gene, which leads to the expression of a toxic gain-of-function mRNA. The expanded CUG repeat mRNA sequesters the MBNL1 splicing regulator in nuclear-retained foci structures, resulting in loss of protein function and disruption of alternative splicing homeostasis. In this study, we used CAG repeat antisense oligonucleotides (ASOs), composed of locked nucleic acid (LNA)- and 2\u2032-\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    -methyl (2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    Me)-modified bases in a chimeric design, to alleviate CUG\n                    <jats:sup>expanded<\/jats:sup>\n                    -mediated toxicity. Chimeric 14\u201318mer LNA\/2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    Me oligonucleotides, exhibiting an LNA incorporation of \u223c33%, significantly ameliorated the misregulated alternative splicing of Mbnl1-dependent exons in primary DM1 mouse myoblasts and tibialis anterior muscles of DM1 mice. Subcutaneous delivery of 14mer and 18mer LNA\/2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    Me chimeras in DM1 mice resulted in high levels of accumulation in all tested skeletal muscles, as well as in the diaphragm and heart tissue. Despite the efficient delivery, chimeric LNA\/2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    Me oligonucleotides were not able, even at a high-dosage regimen (400\u2009mg\/kg\/week), to correct the misregulated splicing of\n                    <jats:italic toggle=\"yes\">Serca1<\/jats:italic>\n                    exon 22 in skeletal muscles. Nevertheless, oligonucleotide doses were well-tolerated as determined by histological and plasma biochemistry analyses. Our results provide proof of concept that inhibition of MBNL1 sequestration by systemic delivery of a steric-blocking ASO is extremely challenging, considering the large number of target sites that need to be occupied per RNA molecule. Although not suitable for DM1 therapy, chimeric LNA\/2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    Me oligonucleotides could prove to be highly beneficial for other diseases, such as Duchenne muscular dystrophy, that require inhibition of a single target site per RNA molecule.\n                  <\/jats:p>","DOI":"10.1089\/nat.2019.0811","type":"journal-article","created":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T11:45:09Z","timestamp":1577187909000},"page":"80-93","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":10,"title":["Systemic Evaluation of Chimeric LNA\/2\u2032-O-Methyl Steric Blockers for Myotonic Dystrophy Type 1 Therapy"],"prefix":"10.1177","volume":"30","author":[{"given":"Melina","family":"Christou","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Function &amp; Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesper","family":"Wengel","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, Biomolecular Nanoscale Engineering Center, University of Southern Denmark, Odense M, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kleitos","family":"Sokratous","sequence":"additional","affiliation":[{"name":"Department of Electron Microscopy and Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."},{"name":"Bioinformatics Group, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyriacos","family":"Kyriacou","sequence":"additional","affiliation":[{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."},{"name":"Department of Electron Microscopy and Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgios","family":"Nikolaou","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory, Vet Ex Machina Ltd, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonidas A.","family":"Phylactou","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Function &amp; Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos P.","family":"Mastroyiannopoulos","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Function &amp; Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,3,26]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70204-1"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.05.019"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1546325"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv029"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00572-5"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600300"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu492"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5364.737"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng704"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11067"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.8.3209"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117860"},{"key":"e_1_3_5_14_2","first-page":"562","article-title":"Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides","volume":"2","author":"Geary RS","year":"2001","unstructured":"Geary RS, , Yu RZ, and Levin AA. 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(2017). Ionis Reports Setback on DMPKRx Program for Myotonic Dystrophy. https:\/\/strongly.mda.org\/"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2012.0404"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02634119"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.09.002"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1173110"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3765"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2012.30"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI128205"},{"key":"e_1_3_5_47_2","unstructured":"Mignon L. (2017). 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