{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:40:57Z","timestamp":1790516457548,"version":"4.1.0"},"reference-count":62,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Here we describe a successful gene therapy approach for hemophilia A (HA), using the natural F8 promoter (pF8) to direct gene replacement to factor VIII (FVIII)\u2013secreting cells. The promoter sequence and the regulatory elements involved in the modulation of F8 expression are still poorly characterized and biased by the historical assumption that FVIII expression is mainly in hepatocytes. Bioinformatic analyses have highlighted an underestimated complexity in gene expression at this locus, suggesting an activation of pF8 in more cell types than those previously expected. C57Bl\/6 mice injected with a lentiviral vector expressing green fluorescent protein (GFP) under the pF8 (lentiviral vector [LV].pF8.GFP) confirm the predominant GFP expression in liver sinusoidal endothelial cells, with a few positive cells detectable also in hematopoietic organs. Therapeutic gene delivery (LV.pF8.FVIII) in hemophilic C57\/Bl6 and 129-Bl6 mice successfully corrected the bleeding phenotype, rescuing up to 25% FVIII activity, using a codon-optimized FVIII, with sustained activity for the duration of the experiment (1 year) without inhibitor formation. Of note, LV.pF8.FVIII delivery in FVIII-immunized HA mice resulted in the complete reversion of the inhibitor titer with the recovery of therapeutic FVIII activity. Depletion of regulatory T cells (Tregs) in LV-treated mice allowed the formation of anti-FVIII antibodies, indicating a role for Tregs in immune tolerance induction. The significant blood loss reduction observed in all LV.pF8.FVIII-treated mice 1 year after injection confirmed the achievement of a long-term phenotypic correction. Altogether, our results highlight the potency of pF8-driven transgene expression to correct the bleeding phenotype in HA, as well as potentially in other diseases in which an endothelial-specific expression is required.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018027979","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T16:45:26Z","timestamp":1552409126000},"page":"825-838","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":30,"title":["FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice"],"prefix":"10.1182","volume":"3","author":[{"given":"Simone","family":"Merlin","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"},{"name":"Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosella","family":"Fam\u00e0","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Borroni","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Zanolini","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Bruscaggin","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Zucchelli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"},{"name":"Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Follenzi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro,\u201d Novara, Italy; and"},{"name":"Interdisciplinary Research Center of Autoimmune Diseases, Novara, 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