{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:44:07Z","timestamp":1768452247552,"version":"3.49.0"},"reference-count":71,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We previously showed that intraosseous (IO) delivery of factor VIII (FVIII, gene F8) lentiviral vector (LV) driven by the megakaryocyte-specific promoter Gp1b\u03b1 (G-F8-LV) partially corrected the bleeding phenotype in hemophilia A (HemA) mice for up to 5 months. In this study, we further characterized and confirmed the successful transduction of self-regenerating hematopoietic stem and progenitor cells (HSPCs) in treated mice. In addition, secondary transplant of HSPCs isolated from G-F8-LV\u2013treated mice corrected the bleeding phenotype of the recipient HemA mice, indicating the potential of long-term transgene expression following IO-LV therapy. To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy into human HSPCs. In\u00a0vitro transduction of human HSPCs by the platelet-targeted G-F8-LV confirmed megakaryocyte-specific gene expression after preferential differentiation of HSPCs to megakaryocyte lineages. Lentiviral integration analysis detected a polyclonal integration pattern in G-F8-LV\u2013transduced human cells, profiling the clinical safety of hemophilia treatment. Most importantly, IO delivery of G-F8-LV to humanized NBSGW mice produced persistent FVIII expression in human platelets after gene therapy, and the megakaryocytes differentiated from human CD34+ HSPCs isolated from LV-treated humanized mice showed up to 10.2% FVIII expression, indicating efficient transduction of self-regenerating human HSPCs. Collectively, these results indicate the long-term safety and efficacy of the IO-LV gene therapy strategy for HemA in a humanized model, adding further evidence to the feasibility of translating this method for clinical applications.<\/jats:p>","DOI":"10.1182\/bloodadvances.2022008079","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T18:37:15Z","timestamp":1658169435000},"page":"5556-5569","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Intraosseous delivery of platelet-targeted factor VIII lentiviral vector in humanized NBSGW mice"],"prefix":"10.1182","volume":"6","author":[{"given":"Julia H.","family":"Joo","sequence":"first","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8842-610X","authenticated-orcid":false,"given":"Xuefeng","family":"Wang","sequence":"additional","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swati","family":"Singh","sequence":"additional","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7199-3271","authenticated-orcid":false,"given":"Chun-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Li","sequence":"additional","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4599-016X","authenticated-orcid":false,"given":"Jennifer E.","family":"Adair","sequence":"additional","affiliation":[{"name":"2Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Peter","family":"Kiem","sequence":"additional","affiliation":[{"name":"2Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Rawlings","sequence":"additional","affiliation":[{"name":"1Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute, Seattle, 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