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Here we show that liver gene therapy by lentiviral vectors (LVs) expressing factor IX (FIX) strongly reduces pre\u2010existing anti\u2010FIX antibodies and eradicates FIX inhibitors in haemophilia B mice. Concomitantly, plasma FIX levels and clotting activity rose to 50\u2013100% of normal. The treatment was effective in 75% of treated mice. FIX\u2010specific plasma cells (PCs) and memory B cells were reduced, likely because of memory B\u2010cell depletion in response to constant exposure to high doses of FIX. Regulatory T cells displaying FIX\u2010specific suppressive capacity were induced in gene therapy treated mice and controlled FIX\u2010specific T helper cells. Gene therapy proved safer than a regimen mimicking immune tolerance induction (ITI) by repeated high\u2010dose FIX protein administration, which induced severe anaphylactoid reactions in inhibitors\u2010positive haemophilia B mice. Liver gene therapy can thus reverse pre\u2010existing immunity, induce active tolerance to FIX and establish sustained FIX activity at therapeutic levels. These data position gene therapy as an attractive treatment option for inhibitors\u2010positive haemophilic patients.<\/jats:p>","DOI":"10.1002\/emmm.201302857","type":"journal-article","created":{"date-parts":[[2013,10,8]],"date-time":"2013-10-08T10:15:02Z","timestamp":1381227302000},"page":"1684-1697","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Liver gene therapy by lentiviral vectors reverses anti\u2010factor IX pre\u2010existing immunity in haemophilic mice"],"prefix":"10.1038","volume":"5","author":[{"given":"Andrea","family":"Annoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Cantore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Della Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Goudy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahzad","family":"Akbarpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bartolaccini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"D'Angelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Roncarolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Naldini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,9,16]]},"reference":[{"key":"BFEMMM201302857_CR1","doi-asserted-by":"crossref","first-page":"5152","DOI":"10.1182\/blood-2009-04-214569","volume":"114","author":"A Annoni","year":"2009","unstructured":"Annoni A, Brown BD, Cantore A, Sergi LS, Naldini L, Roncarolo MG (2009) In vivo delivery of a microRNA\u2010regulated transgene induces antigen\u2010specific regulatory T cells and promotes immunologic tolerance. 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