{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:11:00Z","timestamp":1790349060439,"version":"4.1.0"},"reference-count":46,"publisher":"Georg Thieme Verlag KG","issue":"01","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hamostaseologie"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gene therapy represents a paradigm shift in haemophilia management, offering the potential for sustained factor expression and freedom from prophylactic infusions. Two adeno-associated virus (AAV)\u2013based gene therapies are now approved. Long-term follow-up data demonstrate remarkable durability, with 13-year results showing sustained reductions in annualized bleeding rates in patients with haemophilia B. Outcomes differ between haemophilia A and B: factor VIII levels in haemophilia A decline after peaking, whereas factor IX expression in haemophilia B remains more stable. Recent analyses confirm significant reductions in bleeding rates and treatment requirements, along with well-characterized safety profiles. Liver toxicity remains the primary safety concern, with transaminase elevations typically responding to corticosteroids. Rare adverse events include one reported case of inhibitor development and very few thrombotic events. Reported malignancies to date have not been associated with gene therapy. Current limitations include eligibility restrictions due to preexisting neutralizing antibodies, immune responses to AAV capsids, and variable patient outcomes. These challenges may contribute to slower adoption despite regulatory approval. Emerging approaches such as CRISPR-Cas9 gene editing, high-active factor variants, and novel delivery systems are under investigation. Key implementation issues include outcome-based reimbursement, hub-and-spoke treatment models, and ensuring equitable global access.<\/jats:p>","DOI":"10.1055\/a-2751-7625","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T23:30:27Z","timestamp":1771371027000},"page":"010-016","source":"Crossref","is-referenced-by-count":6,"title":["Gene Therapy of Haemophilia: Current Status and Future Directions"],"prefix":"10.1055","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-0061","authenticated-orcid":false,"given":"Wolfgang","family":"Miesbach","sequence":"additional","affiliation":[{"name":"Department of Coagulation Clinic Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"issue":"09","key":"ref1","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3324\/haematol.2019.221093","article-title":"Hemophilia A and B: molecular and clinical similarities and differences","volume":"104","author":"G Castaman","year":"2019","journal-title":"Haematologica"},{"issue":"08","key":"ref2","doi-asserted-by":"crossref","first-page":"540","DOI":"10.7326\/M19-1208","article-title":"Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries","volume":"171","author":"A Iorio","year":"2019","journal-title":"Ann Intern Med"},{"issue":"S 06","key":"ref4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/hae.14046","article-title":"WFH guidelines for the management of hemophilia, 3rd edition","volume":"26","author":"A Srivastava","year":"2020","journal-title":"Haemophilia"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1055\/a-2411-7416","article-title":"Expert opinion for defining a severe bleeding phenotype to guide prophylaxis in patients with nonsevere hemophilia","author":"C Pfrepper","year":"2024","journal-title":"Hamostaseologie"},{"issue":"13","key":"ref6","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1182\/blood-2015-01-528414","article-title":"Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens","volume":"125","author":"J Oldenburg","year":"2015","journal-title":"Blood"},{"issue":"06","key":"ref7","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1056\/NEJMoa067659","article-title":"Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia","volume":"357","author":"M J Manco-Johnson","year":"2007","journal-title":"N Engl J Med"},{"issue":"05","key":"ref8","doi-asserted-by":"crossref","first-page":"e367","DOI":"10.1111\/hae.13003","article-title":"Adherence to prophylactic treatment in patients with haemophilia in Germany","volume":"22","author":"W Miesbach","year":"2016","journal-title":"Haemophilia"},{"issue":"S 01","key":"ref9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2516.2007.01497.x","article-title":"International workshop on immune tolerance induction: consensus recommendations","volume":"13","author":"D M DiMichele","year":"2007","journal-title":"Haemophilia"},{"issue":"04","key":"ref10","first-page":"100224","article-title":"The World Federation of Hemophilia world bleeding disorders registry 2022","volume":"7","author":"D Coffin","year":"2023","journal-title":"Res Pract Thromb Haemost"},{"issue":"11","key":"ref11","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1182\/blood.2019003777","article-title":"Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues","volume":"138","author":"F WG Leebeek","year":"2021","journal-title":"Blood"},{"issue":"08","key":"ref12","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1182\/blood.V99.8.2670","article-title":"Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy","volume":"99","author":"J D Mount","year":"2002","journal-title":"Blood"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1146\/annurev-med-043021-033013","article-title":"Adeno-associated virus gene therapy for hemophilia","volume":"74","author":"B J Samelson-Jones","year":"2023","journal-title":"Annu Rev Med"},{"issue":"45","key":"ref14","first-page":"105","article-title":"Two decades of clinical gene therapy\u2013success is finally mounting","volume":"9","author":"R W Herzog","year":"2010","journal-title":"Discov Med"},{"issue":"17","key":"ref15","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1056\/NEJMoa0904377","article-title":"X-linked thrombophilia with a mutant factor IX (factor IX Padua)","volume":"361","author":"P Simioni","year":"2009","journal-title":"N Engl J Med"},{"issue":"11","key":"ref17","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1056\/NEJMoa2113708","article-title":"Valoctocogene roxaparvovec gene therapy for hemophilia A","volume":"386","author":"M C Ozelo","year":"2022","journal-title":"N Engl J Med"},{"issue":"14","key":"ref18","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1182\/bloodadvances.2024015291","article-title":"Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years","volume":"9","author":"A von Drygalski","year":"2025","journal-title":"Blood Adv"},{"issue":"12","key":"ref19","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1056\/NEJMoa2302982","article-title":"Gene therapy with fidanacogene elaparvovec in adults with hemophilia B","volume":"391","author":"A Cuker","year":"2024","journal-title":"N Engl J Med"},{"issue":"22","key":"ref21","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1056\/NEJMoa2414783","article-title":"Sustained clinical benefit of AAV gene therapy in severe hemophilia B","volume":"392","author":"U M Reiss","year":"2025","journal-title":"N Engl J Med"},{"issue":"08","key":"ref22","doi-asserted-by":"crossref","first-page":"102615","DOI":"10.1016\/j.rpth.2024.102615","article-title":"Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial","volume":"8","author":"A D Leavitt","year":"2024","journal-title":"Res Pract Thromb Haemost"},{"issue":"08","key":"ref23","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1177\/10600280231202247","article-title":"Valoctocogene roxaparvovec and etranacogene dezaparavovec: novel gene therapies for hemophilia A and B","volume":"58","author":"J A Dougherty","year":"2024","journal-title":"Ann Pharmacother"},{"issue":"02","key":"ref24","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jtha.2022.11.026","article-title":"Liver-related aspects of gene therapy for hemophilia: need for collaborations with hepatologists","volume":"21","author":"W Miesbach","year":"2023","journal-title":"J Thromb Haemost"},{"issue":"02","key":"ref25","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jhep.2023.10.029","article-title":"Adeno-associated viruses for gene therapy - clinical implications and liver-related complications, a guide for hepatologists","volume":"80","author":"M M M\u00fccke","year":"2024","journal-title":"J Hepatol"},{"issue":"07","key":"ref26","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/j.jtha.2025.02.042","article-title":"Corticosteroid use to mitigate transaminitis-associated decline in FVIII levels following valoctocogene roxaparvovec gene therapy: clinical practice guidance","volume":"23","author":"B A Konkle","year":"2025","journal-title":"J Thromb Haemost"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1580264","DOI":"10.3389\/fmed.2025.1580264","article-title":"Adeno-associated virus gene therapy for hemophilia: an update meta-analysis and systematic review","volume":"12","author":"W Yang","year":"2025","journal-title":"Front Med (Lausanne)"},{"issue":"07","key":"ref28","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1016\/j.jtha.2024.04.001","article-title":"Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A","volume":"22","author":"B Madan","year":"2024","journal-title":"J Thromb Haemost"},{"issue":"11","key":"ref29","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1016\/j.jtha.2024.07.012","article-title":"Adeno-associated viral vector integration: implications for long-term efficacy and safety","volume":"22","author":"P Batty","year":"2024","journal-title":"J Thromb Haemost"},{"issue":"17","key":"ref30","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.1182\/bloodadvances.2023009876","article-title":"Molecular evaluation and vector integration analysis of HCC complicating AAV gene therapy for hemophilia B","volume":"7","author":"M Schmidt","year":"2023","journal-title":"Blood Adv"},{"issue":"01","key":"ref31","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1182\/blood-2013-01-306647","article-title":"Immune responses to AAV vectors: overcoming barriers to successful gene therapy","volume":"122","author":"F Mingozzi","year":"2013","journal-title":"Blood"},{"issue":"08","key":"ref32","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1056\/NEJMoa2211644","article-title":"Gene therapy with etranacogene dezaparvovec for hemophilia B","volume":"388","author":"S W Pipe","year":"2023","journal-title":"N Engl J Med"},{"issue":"04","key":"ref33","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1016\/S2352-3026(24)00006-1","article-title":"Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month efficacy and safety data","volume":"11","author":"M Coppens","year":"2024","journal-title":"Lancet Haematol"},{"issue":"03","key":"ref34","doi-asserted-by":"crossref","first-page":"101568","DOI":"10.1016\/j.omtm.2025.101568","article-title":"Natural history of preexisting AAV5 antibodies in adults with hemophilia B during the lead-in of the etranacogene dezaparvovec phase 3 study","volume":"33","author":"R Klamroth","year":"2025","journal-title":"Mol Ther Methods Clin Dev"},{"key":"ref35","doi-asserted-by":"publisher","DOI":"10.1111\/hae.70113","article-title":"The WFH guidelines for the management of haemophilia: AAV gene therapy, 2025","author":"G F Pierce","year":"2025","journal-title":"Haemophilia"},{"key":"ref36","first-page":"S1538","article-title":"A comprehensive care pathway of gene therapy for hemophilia based on current guideline documents and summary of product characteristics: communication from the ISTH SSC working group on gene therapy","author":"C MA Mussert","year":"2025","journal-title":"J Thromb Haemost"},{"issue":"01","key":"ref37","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1111\/hae.14440","article-title":"Implications of haemophilia gene therapy for the changing role of the multidisciplinary team","volume":"28","author":"W Miesbach","year":"2022","journal-title":"Haemophilia"},{"issue":"06","key":"ref38","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/hae.14420","article-title":"Delivery of AAV-based gene therapy through haemophilia centres-a need for re-evaluation of infrastructure and comprehensive care: a joint publication of EAHAD and EHC","volume":"27","author":"W Miesbach","year":"2021","journal-title":"Haemophilia"},{"issue":"03","key":"ref39","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1111\/hae.14546","article-title":"Gene therapy of hemophilia: Hub centres should be haemophilia centres: a joint publication of EAHAD and EHC","volume":"28","author":"W Miesbach","year":"2022","journal-title":"Haemophilia"},{"issue":"05","key":"ref40","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1111\/hae.70090","article-title":"Qualification criteria of gene therapy for haemophilia-opinion of the EAHAD Gene Therapy Working Group","volume":"31","author":"W Miesbach","year":"2025","journal-title":"Haemophilia"},{"issue":"06","key":"ref41","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1111\/hae.14887","article-title":"Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy","volume":"29","author":"A Boban","year":"2023","journal-title":"Haemophilia"},{"issue":"01","key":"ref42","doi-asserted-by":"crossref","first-page":"102673","DOI":"10.1016\/j.rpth.2024.102673","article-title":"Adeno-associated virus-based gene therapy for hemophilia-addressing the gaps","volume":"9","author":"W Miesbach","year":"2024","journal-title":"Res Pract Thromb Haemost"},{"issue":"12","key":"ref43","first-page":"3879","article-title":"Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies","volume":"109","author":"G Di Minno","year":"2024","journal-title":"Haematologica"},{"issue":"05","key":"ref44","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1056\/NEJMoa2410597","article-title":"Lentiviral gene therapy with CD34+ hematopoietic cells for hemophilia A","volume":"392","author":"A Srivastava","year":"2025","journal-title":"N Engl J Med"},{"issue":"01","key":"ref45","doi-asserted-by":"crossref","first-page":"7193","DOI":"10.1038\/s41467-024-51296-8","article-title":"Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice","volume":"15","author":"A R Sternberg","year":"2024","journal-title":"Nat Commun"},{"issue":"21","key":"ref46","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1182\/blood.2023023275","article-title":"Coagulation factor VIII: biological basis of emerging hemophilia A therapies","volume":"144","author":"B J Samelson-Jones","year":"2024","journal-title":"Blood"},{"issue":"01","key":"ref47","doi-asserted-by":"crossref","first-page":"7275","DOI":"10.1038\/s41467-022-34898-y","article-title":"Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response","volume":"13","author":"X He","year":"2022","journal-title":"Nat Commun"},{"issue":"04","key":"ref48","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/hae.14015","article-title":"World Federation of Hemophilia gene therapy registry","volume":"26","author":"B A Konkle","year":"2020","journal-title":"Haemophilia"},{"issue":"05","key":"ref49","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.jtha.2023.12.039","article-title":"Recommendations for a minimum data set for monitoring gene therapy in hemophilia: communication from the ISTH SSC Working Group on Gene Therapy","volume":"22","author":"W Miesbach","year":"2024","journal-title":"J Thromb Haemost"}],"container-title":["H\u00e4mostaseologie"],"original-title":[],"language":"de","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2751-7625.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T23:30:37Z","timestamp":1771371037000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2751-7625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":46,"journal-issue":{"issue":"01","published-online":{"date-parts":[[2026,2,17]]},"published-print":{"date-parts":[[2026,2]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2751-7625","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0720-9355","2567-5761"],"issn-type":[{"value":"0720-9355","type":"print"},{"value":"2567-5761","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]}}}