{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:21:23Z","timestamp":1760145683235,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP1144791"],"award-info":[{"award-number":["APP1144791"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vascular Ehlers\u2013Danlos syndrome or Ehlers\u2013Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and\/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons.<\/jats:p>","DOI":"10.3390\/ijms25168816","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T05:23:27Z","timestamp":1723613007000},"page":"8816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Is Exon Skipping a Viable Therapeutic Approach for Vascular Ehlers\u2013Danlos Syndrome with Mutations in COL3A1 Exon 10 or 15?"],"prefix":"10.3390","volume":"25","author":[{"given":"Sasiwimon","family":"Utama","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand"},{"name":"Centre of Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA 6150, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7218-3027","authenticated-orcid":false,"given":"Jessica M.","family":"Cale","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA 6150, Australia"},{"name":"Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9311-7977","authenticated-orcid":false,"given":"Chalermchai","family":"Mitrpant","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-641X","authenticated-orcid":false,"given":"Sue","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA 6150, Australia"},{"name":"Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve D.","family":"Wilton","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA 6150, Australia"},{"name":"Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6379-2303","authenticated-orcid":false,"given":"May T.","family":"Aung-Htut","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA 6150, Australia"},{"name":"Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31067","DOI":"10.1074\/jbc.M212889200","article-title":"A novel and highly conserved collagen (pro(alpha)1(XXVII)) with a unique expression pattern and unusual molecular characteristics establishes a new clade within the vertebrate fibrillar collagen family","volume":"278","author":"Tuckwell","year":"2003","journal-title":"J. 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