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While most carriers are asymptomatic or mildly affected, severe forms of \u03b1-thalassemia, including severe hemoglobin H (HbH) disease and surviving individuals with Hb Bart\u2019s hydrops fetalis syndrome (BHFS), require lifelong transfusion support or stem cell transplantation. Reactivating the silenced embryonic \u03b1-like globin (\u03b6-globin) gene is a promising approach for treating these diseases. Here we identify the key\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory elements responsible for silencing the \u03b6-globin gene in definitive erythroid cells and subsequently develop gene-editing strategies that reactivate \u03b6-globin expression to therapeutically relevant levels. In a preclinical mouse model of BHFS, we show that this strategy rescues the otherwise prenatal lethal condition until late in development (E17.5). Using primary erythroid cells derived from patients with HbH disease and BHFS, we show that these approaches reactivate \u03b6-globin expression to levels exceeding those achieved in the mouse model, producing therapeutic levels of \u03b1-like globin.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02770-0","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:03:21Z","timestamp":1790845401000},"page":"2619-2629","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reactivation of the embryonic \u03b6-globin gene ameliorates severe forms of \u03b1-thalassemia"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8416-5879","authenticated-orcid":false,"given":"Siyu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayesha","family":"Ejaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1397-654X","authenticated-orcid":false,"given":"Andrew J.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0980-6663","authenticated-orcid":false,"given":"Aude-Anais","family":"Olijnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Sloane-Stanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6926-7502","authenticated-orcid":false,"given":"Ali","family":"Amid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Biggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Eglinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Martyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2057-3642","authenticated-orcid":false,"given":"Merlin","family":"Crossley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1898-5878","authenticated-orcid":false,"given":"Christian","family":"Babbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9781-921X","authenticated-orcid":false,"given":"Mira T.","family":"Kassouf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-8705","authenticated-orcid":false,"given":"Douglas R.","family":"Higgs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2770_CR1","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1038\/321744a0","volume":"321","author":"J Flint","year":"1986","unstructured":"Flint, J. et al. 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Blood 101, 791\u2013800 (2003).","journal-title":"Blood"},{"key":"2770_CR4","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1182\/blood-2016-08-697110","volume":"129","author":"D Songdej","year":"2017","unstructured":"Songdej, D. et al. An international registry of survivors with Hb Bart\u2019s hydrops fetalis syndrome. Blood 129, 1251\u20131259 (2017).","journal-title":"Blood"},{"key":"2770_CR5","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1182\/bloodadvances.2022007823","volume":"7","author":"ME Schwab","year":"2022","unstructured":"Schwab, M. E. et al. The impact of in utero transfusions on perinatal outcomes in patients with \u03b1 thalassemia major: the UCSF registry. Blood Adv. 7, 269\u2013279 (2022).","journal-title":"Blood Adv."},{"key":"2770_CR6","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-026-06855-y","volume":"105","author":"L Huang","year":"2026","unstructured":"Huang, L. et al. Transforming the treatment of \u03b1-thalassemia: a single-center retrospective study on hematopoietic stem cell transplantation in transfusion-dependent pediatric patients. Ann. Hematol. 105, 157 (2026).","journal-title":"Ann. Hematol."},{"key":"2770_CR7","doi-asserted-by":"publisher","first-page":"3057","DOI":"10.1182\/blood.V92.9.3057","volume":"92","author":"JE Russell","year":"1998","unstructured":"Russell, J. E. & Liebhaber, S. A. Reversal of lethal \u03b1- and \u03b2-thalassemias in mice by expression of human embryonic globins. Blood 92, 3057\u20133063 (1998).","journal-title":"Blood"},{"key":"2770_CR8","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1182\/asheducation-2018.1.353","volume":"2018","author":"AJ King","year":"2018","unstructured":"King, A. J. & Higgs, D. R. Potential new approaches to the management of the Hb Bart\u2019s hydrops fetalis syndrome: the most severe form of \u03b1-thalassemia. Hematology Am. Soc. Hematol. Educ. 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Defining genome architecture at base-pair resolution. Nature 595, 125\u2013129 (2021).","journal-title":"Nature"},{"key":"2770_CR18","doi-asserted-by":"publisher","first-page":"2637","DOI":"10.1128\/MCB.16.6.2637","volume":"16","author":"SA Liebhaber","year":"1996","unstructured":"Liebhaber, S. A. et al. Developmental silencing of the embryonic \u03b6-globin gene: concerted action of the promoter and the 3\u2032-flanking region combined with stage-specific silencing by the transcribed segment. Mol. Cell. Biol. 16, 2637\u20132646 (1996).","journal-title":"Mol. Cell. Biol."},{"key":"2770_CR19","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1128\/MCB.18.4.2173","volume":"18","author":"JE Russell","year":"1998","unstructured":"Russell, J. E. et al. Sequence divergence in the 3\u2032 untranslated regions of human \u03b6- and \u03b1-globin mRNAs mediates a difference in their stabilities and contributes to efficient \u03b1-to-\u03b6 gene development switching. Mol. Cell. 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