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Major limitations are the large size of the\n                    <jats:italic>F8<\/jats:italic>\n                    transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti\u2010F8 antibodies which neutralise F8 activity. Taking advantage of split\u2010intein\u2010mediated protein\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010splicing, we divided the coding sequence of the large and highly secreted F8\u2010N6 variant in two separate AAV\u2010intein vectors whose co\u2010administration to HemA mice results in the expression of therapeutic levels of F8 over time. This occurred without eliciting circulating anti\u2010F8 antibodies unlike animals treated with the single oversized AAV\u2010\n                    <jats:italic>F8<\/jats:italic>\n                    vector under clinical development. Therefore, liver gene therapy with AAV\u2010\n                    <jats:italic>F8<\/jats:italic>\n                    \u2010N6 intein should be considered as a potential therapeutic strategy for HemA.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202115199","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T03:15:58Z","timestamp":1651461358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Liver gene therapy with intein\u2010mediated F8 trans\u2010splicing corrects mouse haemophilia A"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8521-4627","authenticated-orcid":false,"given":"Federica","family":"Esposito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5590-3835","authenticated-orcid":false,"given":"Hristiana","family":"Lyubenova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0700-3007","authenticated-orcid":false,"given":"Patrizia","family":"Tornabene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Auricchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8541-8120","authenticated-orcid":false,"given":"Antonella","family":"Iuliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Nusco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5209-3921","authenticated-orcid":false,"given":"Simone","family":"Merlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5738-213X","authenticated-orcid":false,"given":"Cristina","family":"Olgasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5697-2648","authenticated-orcid":false,"given":"Giorgia","family":"Manni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0645-9800","authenticated-orcid":false,"given":"Marco","family":"Gargaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8501-2136","authenticated-orcid":false,"given":"Francesca","family":"Fallarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9780-300X","authenticated-orcid":false,"given":"Antonia","family":"Follenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0832-2472","authenticated-orcid":false,"given":"Alberto","family":"Auricchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,2]]},"reference":[{"key":"BFEMMM202115199_CR1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/humu.1380050102","volume":"5","author":"SE Antonarakis","year":"1995","unstructured":"Antonarakis SE, Kazazian HH, Tuddenham EGD (1995) Molecular etiology of factor VIII deficiency in hemophilia A. 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