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Our laboratory focuses on developing therapeutic splice modulating antisense oligonucleotides to treat diseases potentially amendable to intervention during pre-mRNA processing, and here we report the use of oligomers to down-regulate integrin alpha 4 protein levels. Over one hundred antisense oligonucleotides were designed to induce skipping of individual exons of the <jats:italic>ITGA4<\/jats:italic> transcript and thereby reducing protein expression. Integrin alpha 4-mediated activities were evaluated in human dermal fibroblasts and Jurkat cells, an immortalised human T lymphocyte cell line. Peptide conjugated phosphorodiamidate morpholino antisense oligomers targeting <jats:italic>ITGA4<\/jats:italic> were also assessed for their effect in delaying disease progression in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. With the promising results in ameliorating disease progression, we are optimistic that the candidate oligomer may also be applicable to many other diseases associated with integrin alpha 4 mediated inflammation. This highly specific strategy to down-regulate protein expression through interfering with normal exon selection during pre-mRNA processing should be applicable to many other gene targets that undergo splicing during expression.<\/jats:p>","DOI":"10.1038\/s41598-019-49385-6","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T10:04:12Z","timestamp":1568109852000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Reduction of integrin alpha 4 activity through splice modulating antisense oligonucleotides"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6379-2303","authenticated-orcid":false,"given":"May T.","family":"Aung-Htut","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Comerford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Johnsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerrie","family":"Foyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve D.","family":"Wilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,10]]},"reference":[{"key":"49385_CR1","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1073\/pnas.75.1.280","volume":"75","author":"PC Zamecnik","year":"1978","unstructured":"Zamecnik, P. 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The <i>in vitro<\/i> validation experiments in this manuscript covered patent application. This has not been licensed to any commercial interests. S.F. and S.D.W. are consultants for Sarepta Therapeutics, and M.T.A.-H.\u2019s salary is partly supported by Sarepta Therapeutics. This association has not influenced this work in any fashion.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12994"}}