{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:48:01Z","timestamp":1792784881068,"version":"4.5.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sponsored research agreement by Bioverativ \/ Sanofi"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional &gt;10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application.<\/jats:p>","DOI":"10.1038\/s41467-022-30102-3","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T06:04:08Z","timestamp":1651644248000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0363-678X","authenticated-orcid":false,"given":"Michela","family":"Milani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Canepari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Biffi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Plati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalia","family":"Curto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susannah","family":"Patarroyo-White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Drager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Visigalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Brombin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Albertini","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"}]},{"given":"Eduard","family":"Ayuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8541-2578","authenticated-orcid":false,"given":"Andrea","family":"Annoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-527X","authenticated-orcid":false,"given":"Luigi","family":"Naldini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9741-997X","authenticated-orcid":false,"given":"Alessio","family":"Cantore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,4]]},"reference":[{"key":"30102_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nrd.2018.70","volume":"17","author":"R Peters","year":"2018","unstructured":"Peters, R. & Harris, T. Advances and innovations in haemophilia treatment. Nat. Rev. Drug Discov. 17, 493\u2013508 (2018).","journal-title":"Nat. Rev. Drug Discov."},{"key":"30102_CR2","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1056\/NEJMoa1803550","volume":"379","author":"J Mahlangu","year":"2018","unstructured":"Mahlangu, J. et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N. Engl. J. Med 379, 811\u2013822 (2018).","journal-title":"N. Engl. J. Med"},{"key":"30102_CR3","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMra1706910","volume":"381","author":"KA High","year":"2019","unstructured":"High, K. A. & Roncarolo, M. G. Gene therapy. N. Engl. J. Med. 381, 455\u2013464 (2019).","journal-title":"N. Engl. J. Med."},{"key":"30102_CR4","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1056\/NEJMoa1407309","volume":"371","author":"AC Nathwani","year":"2014","unstructured":"Nathwani, A. C. et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med 371, 1994\u20132004 (2014).","journal-title":"N. Engl. J. Med"},{"key":"30102_CR5","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1056\/NEJMoa1708538","volume":"377","author":"LA George","year":"2017","unstructured":"George, L. A. et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N. Engl. J. Med. 377, 2215\u20132227 (2017).","journal-title":"N. Engl. J. Med."},{"key":"30102_CR6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1056\/NEJMoa1908490","volume":"382","author":"KJ Pasi","year":"2020","unstructured":"Pasi, K. J. et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N. Engl. J. Med 382, 29\u201340 (2020).","journal-title":"N. Engl. J. 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FT and SRSI, through SR-Tiget, have established a research collaboration on liver-directed lentiviral gene therapy of hemophilia with Bioverativ\/Sanofi. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2454"}}