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The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown\/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a Rho\n                    <jats:sup>P23H<\/jats:sup>\n                    knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-25204-3","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T06:03:52Z","timestamp":1629093832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Mirtron-mediated RNA knockdown\/replacement therapy for the treatment of dominant retinitis pigmentosa"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9770-6303","authenticated-orcid":false,"given":"Harry O.","family":"Orlans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2941-4464","authenticated-orcid":false,"given":"Michelle E.","family":"McClements","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0662-1073","authenticated-orcid":false,"given":"Alun R.","family":"Barnard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Martinez-Fernandez de la Camara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-4682","authenticated-orcid":false,"given":"Robert E.","family":"MacLaren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"25204_CR1","doi-asserted-by":"publisher","unstructured":"Verbakel, S. 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The applicant for both patents is the University of Oxford. Patent international application numbers: PCT\/GB2019\/053036 and PCT\/GB2019\/053037. Patent international publications numbers: WO 2020\/084318 A1 and WO 2020\/084319 A1, both published 30\/04\/2020. C.M.F.C. declares no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4934"}}