{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:16:28Z","timestamp":1777436188901,"version":"3.51.4"},"reference-count":80,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gene therapy is reshaping the therapeutic paradigm in hemophilia by enabling sustained endogenous clotting factor production after a single administration. This approach moves disease management beyond lifelong replacement therapy. While clinical trials have demonstrated marked reductions in bleeding rates and treatment burden, real-world implementation has revealed emerging complexities. These include interindividual variability in transgene expression reflected by a progressive reduction in circulating FVIII or FIX activity over time, uncertainty regarding the long-term durability of expression, immune-mediated constraints, and episodes of transaminase elevation. This review addresses a critical transition point in the field: the shift from proof-of-concept efficacy toward integration of gene therapy into long-term hemophilia care. We examine determinants of therapeutic stability, host\u2013vector immune interactions, and mechanisms underlying loss or fluctuation of expression, with emphasis on monitoring strategies and post-therapy management pathways. Immunogenic processes affecting vector transduction, hepatocellular responses, and transgene persistence are discussed alongside current approaches to immune modulation. This review uniquely focuses on post-gene therapy clinical integration rather than vector design or trial outcomes. Beyond direct factor correction, evolving therapeutic concepts targeting coagulation rebalancing and immune regulation are considered within a systems-based framework. Psychosocial adaptation and patient-reported outcomes are also explored, underscoring that therapeutic success extends beyond hemostatic control. In aggregate, these perspectives position gene therapy not as a singular curative event but as a component of an evolving, biologically integrated management strategy. Long-term follow-up translational research (LTFU) and coordinated global efforts will be essential to optimize durability, safety, and equitable access.<\/jats:p>","DOI":"10.3390\/ijms27093922","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene Therapy in Hemophilia: Clinical Advances, Immunological Challenges, and Emerging Therapeutic Perspectives"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2826-6623","authenticated-orcid":false,"given":"Agata","family":"Serrafi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Immunochemistry, Division of Chemistry and Immunochemistry, Wroclaw Medical University, M. Sk\u0142odowskiej-Curie 48\/50, 50-369 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9908-6921","authenticated-orcid":false,"given":"Andrzej","family":"Wasilewski","sequence":"additional","affiliation":[{"name":"Student Scientific Association of Medical Chemistry and Immunochemistry, Wroclaw Medical University, M. Sk\u0142odowskiej-Curie 48\/50, 50-369 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Wawrzkiewicz","sequence":"additional","affiliation":[{"name":"Student Scientific Association of Medical Chemistry and Immunochemistry, Wroclaw Medical University, M. Sk\u0142odowskiej-Curie 48\/50, 50-369 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0161-3012","authenticated-orcid":false,"given":"Anna","family":"Ka\u0142u\u017ca","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunochemistry, Division of Chemistry and Immunochemistry, Wroclaw Medical University, M. Sk\u0142odowskiej-Curie 48\/50, 50-369 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5288-0586","authenticated-orcid":false,"given":"Eliza","family":"Wasilewska","sequence":"additional","affiliation":[{"name":"Department of Allergology, Medical University of Gdansk, 80-214 Gdansk, Poland"},{"name":"Center of Rare Disease, Centre University Hospital, 80-952 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ymthe.2020.12.007","article-title":"Current Clinical Applications of In Vivo Gene Therapy with AAVs","volume":"29","author":"Mendell","year":"2021","journal-title":"Mol. 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