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Here, we describe the potential use of a recombinase-based system to correct the 140\u2009kb inversion of the F8 gene frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we develop a coupled heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from patient-derived induced pluripotent stem cells (iPSCs) of a hemophilic donor, results in 12% correction of the inversion and restores Factor VIII mRNA expression. In this work, we present designer-recombinases as an efficient and specific means towards treatment of monogenic diseases caused by large gene inversions.<\/jats:p>","DOI":"10.1038\/s41467-022-28080-7","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T06:05:12Z","timestamp":1642658712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Correction of a Factor VIII genomic inversion with designer-recombinases"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9335-9749","authenticated-orcid":false,"given":"Felix","family":"Lansing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliya","family":"Mukhametzyanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8660-9690","authenticated-orcid":false,"given":"Teresa","family":"Rojo-Romanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Iwasawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8245-6006","authenticated-orcid":false,"given":"Maciej","family":"Paszkowski-Rogacz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Karpinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Grass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Sonntag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5164-316X","authenticated-orcid":false,"given":"Paul Martin","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9475-9533","authenticated-orcid":false,"given":"Ceren","family":"G\u00fcnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1014-9859","authenticated-orcid":false,"given":"Jenna","family":"Hoersten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5455-4901","authenticated-orcid":false,"given":"Lukas Theo","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Rodriguez-Muela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Kn\u00f6fler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6989-3041","authenticated-orcid":false,"given":"Takanori","family":"Takebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4577-3344","authenticated-orcid":false,"given":"Frank","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,20]]},"reference":[{"key":"28080_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.ejmg.2017.01.002","volume":"60","author":"S Lynn","year":"2017","unstructured":"Lynn, S. et al. 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