{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T20:22:10Z","timestamp":1787948530679,"version":"build-2784847793"},"reference-count":32,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"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":[[2023,12,1]]},"abstract":"<jats:p>\n                    Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) patients to restore dystrophin expression by reframing the disrupted open reading frame of the\n                    <jats:italic toggle=\"yes\">DMD<\/jats:italic>\n                    transcript. However, the treatment efficacy of the already conditionally approved AONs remains low. Aiming to optimize AON efficiency, we assessed exon 53 skipping of the\n                    <jats:italic toggle=\"yes\">DMD<\/jats:italic>\n                    transcript with different chemically modified AONs, all with a phosphorothioate backbone: 2\u2032-O-methyl (2\u2032OMe), locked nucleic acid (LNA)-2\u2032OMe, 2\u2032-fluoro (FRNA), LNA-FRNA, \u03b1LNA-FRNA, and FANA-LNA-FRNA. Efficient exon 53 skipping was observed with the FRNA, LNA-FRNA, and LNA-2\u2032OMe AONs in human control myoblast cultures. Weekly subcutaneous injections (50\u2009mg\/kg AON) for a duration of 6 weeks were well tolerated by hDMDdel52\/\n                    <jats:italic toggle=\"yes\">mdx<\/jats:italic>\n                    males. Treatment with the LNA-FRNA and LNA-2\u2032OMe AONs resulted in pronounced exon 53 skip levels in skeletal muscles and heart up to 90%, but no dystrophin restoration was observed. This discrepancy was mainly ascribed to the strong binding nature of LNA modifications to RNA, thereby interfering with the amplification of the unskipped product resulting in artificial overamplification of the exon 53 skip product. Our study highlights that treatment effect on RNA and protein level should both be considered when assessing AON efficiency.\n                  <\/jats:p>","DOI":"10.1089\/nat.2023.0038","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T10:18:19Z","timestamp":1701080299000},"page":"348-360","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":17,"title":["Challenges of Assessing Exon 53 Skipping of the Human\n                    <i>DMD<\/i>\n                    Transcript with Locked Nucleic Acid-Modified Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy"],"prefix":"10.1177","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5358-8691","authenticated-orcid":false,"given":"Sarah","family":"Engelbeen","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"O'reilly","sequence":"additional","affiliation":[{"name":"University of Massachusetts Chan Medical School, RNA Therapeutics Institute, Worcester, Massachusetts, USA."},{"name":"Department of Chemistry, McGill University, Montreal, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davy","family":"van de Vijver","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7348-7989","authenticated-orcid":false,"given":"Ingrid","family":"Verhaart","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike","family":"van Putten","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vignesh","family":"Hariharan","sequence":"additional","affiliation":[{"name":"University of Massachusetts Chan Medical School, RNA Therapeutics Institute, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hassler","sequence":"additional","affiliation":[{"name":"University of Massachusetts Chan Medical School, RNA Therapeutics Institute, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Khvorova","sequence":"additional","affiliation":[{"name":"University of Massachusetts Chan Medical School, RNA Therapeutics Institute, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masad J.","family":"Damha","sequence":"additional","affiliation":[{"name":"Department of Chemistry, McGill University, Montreal, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1565-654X","authenticated-orcid":false,"given":"Annemieke","family":"Aartsma-Rus","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70271-6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30024-3"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90579-4"},{"key":"e_1_3_4_5_2","first-page":"498","article-title":"The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion","volume":"45","author":"Koenig M","year":"1989","unstructured":"Koenig M, , Beggs AH, , Moyer M, , Scherpf S, , Heindrich K, , Bettecken T, , Meng G, , M\u00fcller CR, , Lindl\u00f6f M, et al. (1989). The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. 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