{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:24:16Z","timestamp":1792722256559,"version":"4.5.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"34","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,8,21]]},"abstract":"<jats:p>\n                    Duchenne muscular dystrophy (DMD), the commonest form of muscular dystrophy, is caused by lack of dystrophin. One of the most promising therapeutic approaches is antisense-mediated elimination of frame-disrupting mutations by exon skipping. However, this approach faces two major hurdles: limited applicability of each individual target exon and uncertain function and stability of each resulting truncated dystrophin. Skipping of exons 45\u201355 at the mutation hotspot of the\n                    <jats:italic>DMD<\/jats:italic>\n                    gene would address both issues. Theoretically it could rescue more than 60% of patients with deletion mutations. Moreover, spontaneous deletions of this specific region are associated with asymptomatic or exceptionally mild phenotypes. However, such multiple exon skipping of exons 45\u201355 has proved technically challenging. We have therefore designed antisense oligo (AO) morpholino mixtures to minimize self- or heteroduplex formation. These were tested as conjugates with cell-penetrating moieties (vivo-morpholinos). We have tested the feasibility of skipping exons 45\u201355 in\n                    <jats:italic>H2K-mdx52<\/jats:italic>\n                    myotubes and in\n                    <jats:italic>mdx52<\/jats:italic>\n                    mice, which lack exon 52. Encouragingly, with mixtures of 10 AOs, we demonstrated skipping of all 10 exons in vitro, in\n                    <jats:italic>H2K-mdx52<\/jats:italic>\n                    myotubes and on intramuscular injection into\n                    <jats:italic>mdx52<\/jats:italic>\n                    mice. Moreover, in\n                    <jats:italic>mdx52<\/jats:italic>\n                    mice in vivo, systemic injections of 10 AOs induced extensive dystrophin expression at the subsarcolemma in skeletal muscles throughout the body, producing up to 15% of wild-type dystrophin protein levels, accompanied by improved muscle strength and histopathology without any detectable toxicity. This is a unique successful demonstration of effective rescue by exon 45\u201355 skipping in a dystrophin-deficient animal model.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1204638109","type":"journal-article","created":{"date-parts":[[2012,8,6]],"date-time":"2012-08-06T22:50:06Z","timestamp":1344293406000},"page":"13763-13768","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":150,"title":["Bodywide skipping of exons 45\u201355 in dystrophic\n                    <i>mdx52<\/i>\n                    mice by systemic antisense delivery"],"prefix":"10.1073","volume":"109","author":[{"given":"Yoshitsugu","family":"Aoki","sequence":"first","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"},{"name":"Research Center for Genetic Medicine, Children\u2019s National Medical Center, Washington DC 20010;"},{"name":"Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry and"},{"name":"The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, University of Alberta, Edmonton, AB, T6G 2H7 Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"},{"name":"Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto 390-8621, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tanihata","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"},{"name":"Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Shinjuku, Tokyo 162-8666, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M. R.","family":"Duguez","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Medicine, Children\u2019s National Medical Center, Washington DC 20010;"},{"name":"Th\u00e9rapie des Maladies du Muscle Stri\u00e9, Institut de Myologie Unit\u00e9 Mixte de Recherche en Sant\u00e9 974, Universit\u00e9 Pierre et Marie Curie Paris 6, Unit\u00e9 974, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 Mixte de Recherche 7215, Centre National de la Recherche Scientifique, Association Institut de Myologie 47, 75651 Paris cedex 13, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanneboyina","family":"Nagaraju","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Medicine, Children\u2019s National Medical Center, Washington DC 20010;"},{"name":"Department of Integrative Systems Biology, George Washington University School of Medicine, Washington DC 20010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric P.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Medicine, Children\u2019s National Medical Center, Washington DC 20010;"},{"name":"Department of Integrative Systems Biology, George Washington University School of Medicine, Washington DC 20010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence","family":"Partridge","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Medicine, Children\u2019s National Medical Center, Washington DC 20010;"},{"name":"Department of Integrative Systems Biology, George Washington University School of Medicine, Washington DC 20010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin'ichi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,8,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.363.541"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90579-4"},{"key":"e_1_3_3_3_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":"M Koenig, et al., The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion. 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