{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:03:08Z","timestamp":1792803788610,"version":"4.5.0"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["847826"],"award-info":[{"award-number":["847826"]}]},{"name":"Centre National de la Recherche Scientifique","award":["847826"],"award-info":[{"award-number":["847826"]}],"id":[{"id":"https:\/\/ror.org\/02feahw73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"nstitut National de la sant\u00e9 et la recherche m\u00e9dicale","award":["847826"],"award-info":[{"award-number":["847826"]}]},{"name":"Universit\u00e9 Paris-Saclay (France)","award":["847826"],"award-info":[{"award-number":["847826"]}],"id":[{"id":"https:\/\/ror.org\/03xjwb503","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Paris Ile-de-France Region","award":["847826"],"award-info":[{"award-number":["847826"]}]},{"name":"Minist\u00e8re de l\u2019Enseignement Sup\u00e9rieur et de la Recherche (France)","award":["847826"],"award-info":[{"award-number":["847826"]}],"id":[{"id":"https:\/\/ror.org\/03sjk9a61","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Delivery of Antisense RNA Therapeutics (DARTER)","award":["847826"],"award-info":[{"award-number":["847826"]}]},{"name":"Muscular Dystrophy UK (MDUK)","award":["847826"],"award-info":[{"award-number":["847826"]}],"id":[{"id":"https:\/\/ror.org\/02zcamj98","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Nucleic acid-based therapies have demonstrated great potential for the treatment of monogenetic diseases, including neurologic disorders. To date, regulatory approval has been received for a dozen antisense oligonucleotides (ASOs); however, these chemistries cannot readily cross the blood\u2013brain barrier when administered systemically. Therefore, an investigation of their potential effects within the central nervous system (CNS) requires local delivery. Here, we studied the brain distribution and exon-skipping efficacy of two ASO chemistries, PMO and tcDNA, when delivered to the cerebrospinal fluid (CSF) of mice carrying a deletion in exon 52 of the dystrophin gene, a model of Duchenne muscular dystrophy (DMD). Following intracerebroventricular (ICV) delivery (unilateral, bilateral, bolus vs. slow rate, repeated via cannula or very slow via osmotic pumps), ASO levels were quantified across brain regions and exon 51 skipping was evaluated, revealing that tcDNA treatment invariably generates comparable or more skipping relative to that with PMO, even when the PMO was administered at higher doses. We also performed intra-cisterna magna (ICM) delivery as an alternative route for CSF delivery and found a biased distribution of the ASOs towards posterior brain regions, including the cerebellum, hindbrain, and the cervical part of the spinal cord. Finally, we combined both ICV and ICM injection methods to assess the potential of an additive effect of this methodology in inducing efficient exon skipping across different brain regions. Our results provide useful insights into the local delivery and associated efficacy of ASOs in the CNS in mouse models of DMD. These findings pave the way for further ASO-based therapy application to the CNS for neurological disease.<\/jats:p>","DOI":"10.3390\/cells12060908","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Investigating the Impact of Delivery Routes for Exon Skipping Therapies in the CNS of DMD Mouse Models"],"prefix":"10.3390","volume":"12","author":[{"given":"Amel","family":"Saoudi","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France"},{"name":"Universit\u00e9 Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91400 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Fergus","sequence":"additional","affiliation":[{"name":"School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-6822","authenticated-orcid":false,"given":"Talia","family":"Gileadi","sequence":"additional","affiliation":[{"name":"Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Montanaro","sequence":"additional","affiliation":[{"name":"Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7067-5407","authenticated-orcid":false,"given":"Vincent P.","family":"Kelly","sequence":"additional","affiliation":[{"name":"School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Tensorer","sequence":"additional","affiliation":[{"name":"SQY Therapeutics-Synthena, UVSQ, 78180 Montigny le Bretonneux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Garcia","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-8185","authenticated-orcid":false,"given":"Cyrille","family":"Vaillend","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91400 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Muntoni","sequence":"additional","affiliation":[{"name":"Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-1165","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Goyenvalle","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1093\/nar\/25.18.3615","article-title":"Kinetics of Phosphorothioate Oligonucleotide Metabolism in Biological Fluids","volume":"25","author":"Gilar","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1039\/C4SC03990D","article-title":"Ruthenium-Caged Antisense Morpholinos for Regulating Gene Expression in Zebrafish Embryos","volume":"6","author":"Griepenburg","year":"2015","journal-title":"Chem. 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