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Conversely, genome editing by precise gene correction or targeted transgene insertion could be translated to children and even neonates. Pioneer studies with Zinc\u2010Finger nucleases (ZFN) driving homologous directed repair (HDR) established the proof of concept for in vivo targeted integration. The advent of the much more versatile CRISPR\u2010Cas9 technology boosted research in the haemophilia field, and preclinical data demonstrated that targeted gene insertion of the\n                      <jats:italic>F8\/F9<\/jats:italic>\n                      coding sequence, can represent a durable therapy both in adults and neonates. Although with modest efficiency, the effect can be boosted by exploitation of the hyperactive FIX\n                      <jats:sup>Padua<\/jats:sup>\n                      and\/or integration at a \u201csmart\u201d target locus of a highly expressed liver\u2010specific gene such as\n                      <jats:italic>Albumin<\/jats:italic>\n                      (Phase 1\/2 trial). Moreover, targeted insertion has been achieved at the CCR5 locus to insert the FIX\n                      <jats:sup>Padua<\/jats:sup>\n                      via HDR in B lymphocytes, and this promising ex\u2010vivo gene therapy entered a Phase 1\/2 trial. Base and prime editors have also been successfully exploited in cellular models to precisely correct gene defects but their translational potential is limited by the many diverse haemophilia\u2010causing genetic variants that need to be addressed. As these technologies mature, rigorous long\u2010term follow\u2010up and safety monitoring will be essential to offer patients a definitive cure for haemophilia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/hae.70238","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T10:16:31Z","timestamp":1776334591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene Editing for Haemophilia\u2014The Next Frontier"],"prefix":"10.1111","author":[{"given":"Mirko","family":"Pinotti","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Biotechnology University of Ferrara  Ferrara Emilia\u2010Romagna Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A.","family":"Newby","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Institute of NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sundar","family":"Selvaraj","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven W.","family":"Pipe","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Pathology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011847"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17474086.2023.2276206"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.03.043"},{"key":"e_1_2_13_5_1","unstructured":"CRISPR Medicine News Clinical Trials Register.2026 https:\/\/crisprmedicinenews.com\/clinical\u2010trials\/."},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309676"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/20406207251387402"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2025.10"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-017-0352-4"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-024-00654-5"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.114"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10177"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-12-615492"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.10.010"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1978-5"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000790"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.06.025"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-024-00705-1"},{"issue":"1","key":"e_1_2_13_19_1","first-page":"7","article-title":"CRISPR\/Cas9\u2010Mediated Targeted Insertion of Human F9 Achieves Therapeutic Circulating Protein Levels in Mice and NonHuman Primates","volume":"27","author":"Huang H.\u2010R.","year":"2019","journal-title":"Molecular Therapy"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2023.03.008"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20565"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2024.04.009"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101619"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34898-y"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj6901"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1711-4"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00541-1"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.08.076"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-023-00286-w"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.04.020"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024027870"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1699-x"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgeed.2022.785698"},{"issue":"2","key":"e_1_2_13_34_1","first-page":"3","article-title":"CRISPR\/Cas9\u2010Based Gene Editing for Haemophilia B: Durable Pre\u2010Clinical Expression of Factor IX","volume":"29","author":"Gutstein D. 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