{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:13:50Z","timestamp":1790723630469,"version":"4.1.0"},"reference-count":88,"publisher":"Georg Thieme Verlag KG","issue":"01","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Thromb Hemost"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Strides in advancements of care of persons with hemophilia include development of long-acting factor replacement therapies, novel substitution and hemostatic rebalancing agents, and most recently approved gene therapy. Several decades of preclinical and clinical trials have led to development of adeno-associated viral (AAV) vector-mediated gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA). Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant improvement in bleeding rates and use of factor replacement therapy; however, sustainability and duration of response show variability with overall decline in FVIII expression over time. Further challenges include untoward adverse effects involving liver toxicity requiring immunosuppression and development of neutralizing antibodies to AAV vector rendering future doses ineffective. Real-life applicability of gene therapy for HA will require appropriate patient screening, infrastructure setup, long-term monitoring including data collection of patient-reported outcomes and innovative payment schemes. This review article highlights the success and development of HA gene therapy trials, challenges including adverse outcomes and variability of response, and perspectives on approach to gene therapy including shared decision-making and need for future strategies to overcome the several unmet needs.<\/jats:p>","DOI":"10.1055\/s-0044-1785483","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T23:04:18Z","timestamp":1712617458000},"page":"028-040","source":"Crossref","is-referenced-by-count":10,"title":["Gene Therapy in Hemophilia A: Achievements, Challenges, and Perspectives"],"prefix":"10.1055","volume":"51","author":[{"given":"Natasha S.","family":"Bala","sequence":"additional","affiliation":[{"name":"Rady Children's Hospital San Diego, Hemophilia and Thrombosis Treatment Center, San Diego, California"},{"name":"Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney D.","family":"Thornburg","sequence":"additional","affiliation":[{"name":"Rady Children's Hospital San Diego, Hemophilia and Thrombosis Treatment Center, San Diego, California"},{"name":"Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"issue":"01","key":"ref1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-021-00278-x","article-title":"Haemophilia","volume":"7","author":"E Berntorp","year":"2021","journal-title":"Nat Rev Dis Primers"},{"issue":"01","key":"ref2","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13023-022-02300-1","article-title":"Differential humanistic and economic burden of mild, moderate and severe haemophilia in European adults: a regression analysis of the CHESS II study","volume":"17","author":"I Rodriguez-Santana","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1182\/asheducation-2013.1.52","article-title":"What is the role of prophylaxis in the improvement of health-related quality of life of patients with hemophilia?","volume":"2013","author":"D Buchbinder","year":"2013","journal-title":"Hematology (Am Soc Hematol Educ Program)"},{"issue":"01","key":"ref4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s13023-023-02690-w","article-title":"The impact of bleeding event frequency on health-related quality of life and work productivity outcomes in a European cohort of adults with haemophilia A: insights from the CHESS II study","volume":"18","author":"L Young","year":"2023","journal-title":"Orphanet J Rare Dis"},{"issue":"05","key":"ref5","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/j.1365-2516.2012.02791.x","article-title":"Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va)","volume":"18","author":"J L Poon","year":"2012","journal-title":"Haemophilia"},{"issue":"03","key":"ref6","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/hae.13754","article-title":"From the voices of people with haemophilia A and their caregivers: challenges with current treatment, their impact on quality of life and desired improvements in future therapies","volume":"25","author":"R E Wiley","year":"2019","journal-title":"Haemophilia"},{"issue":"S 05","key":"ref7","first-page":"s126","article-title":"Economic costs of hemophilia and the impact of prophylactic treatment on patient management","volume":"22","author":"S L Chen","year":"2016","journal-title":"Am J Manag Care"},{"issue":"05","key":"ref8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1182\/blood-2018-08-872291","article-title":"New therapies for hemophilia","volume":"133","author":"A C Weyand","year":"2019","journal-title":"Blood"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/S0140-6736(20)32722-7","article-title":"The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing","volume":"397","author":"M E Mancuso","year":"2021","journal-title":"Lancet"},{"issue":"04","key":"ref10","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1056\/NEJMoa2209226","article-title":"Efanesoctocog Alfa prophylaxis for patients with severe hemophilia A","volume":"388","author":"A von Drygalski","year":"2023","journal-title":"N Engl J Med"},{"issue":"09","key":"ref12","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1056\/NEJMoa1803550","article-title":"Emicizumab prophylaxis in patients who have hemophilia A without inhibitors","volume":"379","author":"J Mahlangu","year":"2018","journal-title":"N Engl J Med"},{"issue":"S 01","key":"ref13","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1182\/blood-2019-128083","article-title":"Patterns and predictors of emicizumab adherence in people with hemophilia","volume":"134","author":"A Li","year":"2019","journal-title":"Blood"},{"issue":"S 01","key":"ref14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1182\/blood-2020-137632","article-title":"Real-world persistence with and adherence to emicizumab prophylaxis in persons with hemophilia a: a secondary claims database analysis","volume":"136","author":"A Mahajerin","year":"2020","journal-title":"Blood"},{"issue":"03","key":"ref15","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/hae.14755","article-title":"Assessment of the clinical perception, quality of life and satisfaction of patients with severe congenital haemophilia A without inhibitor after 1 year of emicizumab therapy","volume":"29","author":"G Oka","year":"2023","journal-title":"Haemophilia"},{"issue":"S 01","key":"ref16","doi-asserted-by":"crossref","first-page":"4248","DOI":"10.1182\/blood-2021-152936","article-title":"Use of emicizumab in patients with hemophilia A with and without inhibitors: a single center experience","volume":"138","author":"G Giuffrida","year":"2021","journal-title":"Blood"},{"issue":"10","key":"ref17","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.3390\/ph15101183","article-title":"Updates on novel non-replacement drugs for hemophilia","volume":"15","author":"R Gualtierotti","year":"2022","journal-title":"Pharmaceuticals (Basel)"},{"issue":"01","key":"ref18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/hae.13862","article-title":"Achieving the unimaginable: health equity in haemophilia","volume":"26","author":"M W Skinner","year":"2020","journal-title":"Haemophilia"},{"issue":"05","key":"ref19","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s40259-023-00615-4","article-title":"Evaluating gene therapy as a potential paradigm shift in treating severe hemophilia","volume":"37","author":"C D Thornburg","year":"2023","journal-title":"BioDrugs"},{"issue":"03","key":"ref20","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.jtha.2022.12.029","article-title":"Hemophilia treatment innovation: 50 years of progress and more to come","volume":"21","author":"P M Mannucci","year":"2023","journal-title":"J Thromb Haemost"},{"issue":"01","key":"ref21","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1182\/hematology.2022000388","article-title":"Gene therapy for hemophilia","volume":"2022","author":"A C Nathwani","year":"2022","journal-title":"Hematology (Am Soc Hematol Educ Program)"},{"issue":"11","key":"ref22","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"},{"key":"ref23","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":"09","key":"ref24","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1080\/14712598.2022.2002842","article-title":"Hemophilia A gene therapy: current and next-generation approaches","volume":"22","author":"S W Pipe","year":"2022","journal-title":"Expert Opin Biol Ther"},{"issue":"5992","key":"ref25","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/312326a0","article-title":"Characterization of the human factor VIII gene","volume":"312","author":"J Gitschier","year":"1984","journal-title":"Nature"},{"issue":"5992","key":"ref26","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/312342a0","article-title":"Molecular cloning of a cDNA encoding human antihaemophilic factor","volume":"312","author":"J J Toole","year":"1984","journal-title":"Nature"},{"issue":"26","key":"ref27","doi-asserted-by":"crossref","first-page":"8343","DOI":"10.1021\/bi00374a001","article-title":"Construction and characterization of an active factor VIII variant lacking the central one-third of the molecule","volume":"25","author":"D L Eaton","year":"1986","journal-title":"Biochemistry"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S1525-0016(03)00073-X","article-title":"Efficient production of human FVIII in hemophilic mice using lentiviral vectors","volume":"7","author":"N A Kootstra","year":"2003","journal-title":"Mol Ther"},{"issue":"03","key":"ref29","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1182\/blood.V96.3.1173.015k34_1173_1176","article-title":"Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver","volume":"96","author":"F Park","year":"2000","journal-title":"Blood"},{"issue":"11","key":"ref30","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1089\/10430349950017473","article-title":"In vivo evaluation of an adenoviral vector encoding canine factor VIII: high-level, sustained expression in hemophiliac mice","volume":"10","author":"A M Gallo-Penn","year":"1999","journal-title":"Hum Gene Ther"},{"issue":"11","key":"ref31","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1089\/104303402760128559","article-title":"Evaluation of the duration of human factor VIII expression in nonhuman primates after systemic delivery of an adenoviral vector","volume":"13","author":"J L Andrews","year":"2002","journal-title":"Hum Gene Ther"},{"issue":"18","key":"ref32","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1089\/10430349950016401","article-title":"Adenoviral vector-mediated expression of physiologic levels of human factor VIII in nonhuman primates","volume":"10","author":"T Brann","year":"1999","journal-title":"Hum Gene Ther"},{"issue":"23","key":"ref33","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1056\/NEJM200106073442301","article-title":"Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A","volume":"344","author":"D A Roth","year":"2001","journal-title":"N Engl J Med"},{"issue":"06","key":"ref34","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1182\/blood-2003-01-0167","article-title":"Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion","volume":"102","author":"J S Powell","year":"2003","journal-title":"Blood"},{"issue":"S 06","key":"ref35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/hae.13494","article-title":"Haemophilia gene therapy: From trailblazer to gamechanger","volume":"24","author":"H Evens","year":"2018","journal-title":"Haemophilia"},{"issue":"05","key":"ref36","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1182\/blood-2002-03-0823","article-title":"Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors","volume":"101","author":"M K Chuah","year":"2003","journal-title":"Blood"},{"issue":"04","key":"ref37","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1089\/hum.2006.17.427","article-title":"Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice","volume":"17","author":"R Sarkar","year":"2006","journal-title":"Hum Gene Ther"},{"issue":"01","key":"ref38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1182\/blood-2005-12-5115","article-title":"Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs","volume":"108","author":"H Jiang","year":"2006","journal-title":"Blood"},{"issue":"02","key":"ref39","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/j.1538-7836.2007.02346.x","article-title":"Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A","volume":"5","author":"Q Shi","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"26","key":"ref40","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1056\/NEJMoa1708483","article-title":"AAV5-Factor VIII gene transfer in severe hemophilia A","volume":"377","author":"S Rangarajan","year":"2017","journal-title":"N Engl J Med"},{"issue":"11","key":"ref41","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":"08","key":"ref45","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1056\/NEJMoa2211075","article-title":"Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A","volume":"388","author":"J Mahlangu","year":"2023","journal-title":"N Engl J Med"},{"issue":"01","key":"ref46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1056\/NEJMoa1908490","article-title":"Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A","volume":"382","author":"K J Pasi","year":"2020","journal-title":"N Engl J Med"},{"issue":"S 02","key":"ref47","doi-asserted-by":"crossref","first-page":"100459","DOI":"10.1016\/j.rpth.2023.100459","article-title":"Bleeding, FVIII activity, and safety 3 years after gene transfer with valoctocogene roxaparvovec: results from GENEr8-1","volume":"7","author":"J Mahlangu","year":"2023","journal-title":"Res Pract Thromb Haemost"},{"issue":"12","key":"ref48","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.1016\/j.jtha.2023.08.032","article-title":"Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1","volume":"21","author":"B O'Mahony","year":"2023","journal-title":"J Thromb Haemost"},{"issue":"02","key":"ref50","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/hae.14936","article-title":"Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment","volume":"30","author":"E Symington","year":"2024","journal-title":"Haemophilia"},{"issue":"17","key":"ref51","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":"09","key":"ref53","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1182\/blood.2022018971","article-title":"Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1\/2 Alta study","volume":"143","author":"A D Leavitt","year":"2024","journal-title":"Blood"},{"key":"ref54","first-page":"23","article-title":"Gene therapy in Hemophilia: a transformational patient experience","volume":"10","author":"E Rasul","year":"2023","journal-title":"J Patient Exp"},{"issue":"03","key":"ref56","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/rth2.12494","article-title":"Patient selection for hemophilia gene therapy: real-life data from a single center","volume":"5","author":"E Krumb","year":"2021","journal-title":"Res Pract Thromb Haemost"},{"issue":"03","key":"ref57","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/hae.14774","article-title":"Expectation and loss when gene therapy for haemophilia is not an option: an exigency sub-study","volume":"29","author":"S Fletcher","year":"2023","journal-title":"Haemophilia"},{"issue":"01","key":"ref59","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/2040620712464509","article-title":"Factor VIII inhibitors in hemophilia A: rationale and latest evidence","volume":"4","author":"C Witmer","year":"2013","journal-title":"Ther Adv Hematol"},{"issue":"06","key":"ref60","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1182\/blood-2011-08-369132","article-title":"The principal results of the International Immune Tolerance Study: a randomized dose comparison","volume":"119","author":"C R Hay","year":"2012","journal-title":"Blood"},{"issue":"16","key":"ref61","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1182\/blood.2022017780","article-title":"Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study","volume":"141","author":"L Malec","year":"2023","journal-title":"Blood"},{"issue":"01","key":"ref62","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/hae.14192","article-title":"Real-world data of immune tolerance induction using recombinant factor VIII Fc fusion protein in patients with severe haemophilia A with inhibitors at high risk for immune tolerance induction failure: a follow-up retrospective analysis","volume":"27","author":"M Carcao","year":"2021","journal-title":"Haemophilia"},{"issue":"03","key":"ref63","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/hae.12621","article-title":"Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment","volume":"21","author":"S R Earnshaw","year":"2015","journal-title":"Haemophilia"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1089\/hum.2021.287","article-title":"Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A","volume":"33","author":"R Klamroth","year":"2022","journal-title":"Hum Gene Ther"},{"issue":"08","key":"ref67","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":"08","key":"ref68","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1182\/bloodadvances.2022008948","article-title":"Valoctocogene roxaparvovec gene transfer in participants with HIV","volume":"7","author":"M V Ragni","year":"2023","journal-title":"Blood Adv"},{"issue":"01","key":"ref69","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/hae.14188","article-title":"Parental perspectives on gene therapy for children with haemophilia: The Exigency study","volume":"27","author":"K Khair","year":"2021","journal-title":"Haemophilia"},{"issue":"S 04","key":"ref70","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/hae.14545","article-title":"Gene therapy: practical aspects of implementation","volume":"28","author":"S W Pipe","year":"2022","journal-title":"Haemophilia"},{"issue":"02","key":"ref71","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":"04","key":"ref72","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/hae.14309","article-title":"Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU","volume":"27","author":"W Miesbach","year":"2021","journal-title":"Haemophilia"},{"issue":"06","key":"ref73","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":"06","key":"ref74","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1111\/hae.14867","article-title":"Delivery of gene therapy in haemophilia treatment centres in the United States: practical aspects of preparedness and implementation","volume":"29","author":"S Pipe","year":"2023","journal-title":"Haemophilia"},{"issue":"10","key":"ref75","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1038\/nbt1007-1111","article-title":"AAV vectors and tumorigenicity","volume":"25","author":"M A Kay","year":"2007","journal-title":"Nat Biotechnol"},{"issue":"01","key":"ref76","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/hae.14912","article-title":"Landmark endorsement of a global registry: The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP), publicly endorses World Federation of Hemophilia Gene Therapy Registry as global standard","volume":"30","author":"B A Konkle","year":"2024","journal-title":"Haemophilia"},{"issue":"02","key":"ref77","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1080\/03007995.2022.2133492","article-title":"Comprehensive analysis and prediction of long-term durability of factor IX activity following etranacogene dezaparvovec gene therapy in the treatment of hemophilia B","volume":"39","author":"J Shah","year":"2023","journal-title":"Curr Med Res Opin"},{"issue":"20","key":"ref78","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1182\/bloodadvances.2021004760","article-title":"Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?","volume":"5","author":"V R Arruda","year":"2021","journal-title":"Blood Adv"},{"issue":"S 01","key":"ref79","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/ijlh.13605","article-title":"Gene therapy for hemophilia: current status and laboratory consequences","volume":"43","author":"P Batty","year":"2021","journal-title":"Int J Lab Hematol"},{"issue":"14","key":"ref81","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1182\/bloodadvances.2018021345","article-title":"Gene therapy in hemophilia A: a cost-effectiveness analysis","volume":"2","author":"N Machin","year":"2018","journal-title":"Blood Adv"},{"issue":"05","key":"ref82","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1080\/13696998.2020.1721508","article-title":"Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A","volume":"23","author":"K Cook","year":"2020","journal-title":"J Med Econ"},{"issue":"02","key":"ref83","doi-asserted-by":"crossref","first-page":"e679","DOI":"10.1097\/HS9.0000000000000679","article-title":"Modeling benefits, costs, and affordability of a novel gene therapy in hemophilia A","volume":"6","author":"R MT Ten Ham","year":"2022","journal-title":"HemaSphere"},{"issue":"04","key":"ref84","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1111\/hae.14818","article-title":"Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis","volume":"29","author":"J Astermark","year":"2023","journal-title":"Haemophilia"},{"issue":"S 02","key":"ref85","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/hae.14511","article-title":"A preliminary application of a haemophilia value framework to emerging therapies in haemophilia","volume":"28","author":"M W Skinner","year":"2022","journal-title":"Haemophilia"},{"key":"ref87","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.2147\/PPA.S406894","article-title":"Gene therapy for hemophilia A: a mixed methods study of patient preferences and shared decision-making","volume":"17","author":"J Limjoco","year":"2023","journal-title":"Patient Prefer Adherence"},{"issue":"01","key":"ref88","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s13023-022-02256-2","article-title":"The experiences of people with haemophilia and their families of gene therapy in a clinical trial setting: regaining control, the Exigency study","volume":"17","author":"S Fletcher","year":"2022","journal-title":"Orphanet J Rare Dis"},{"issue":"04","key":"ref89","doi-asserted-by":"crossref","first-page":"e167","DOI":"10.1111\/hae.13504","article-title":"Core outcome set for gene therapy in haemophilia: results of the coreHEM multistakeholder project","volume":"24","author":"A Iorio","year":"2018","journal-title":"Haemophilia"},{"issue":"05","key":"ref90","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/hae.14378","article-title":"An exploration of why men with severe haemophilia might not want gene therapy: The exigency study","volume":"27","author":"S Fletcher","year":"2021","journal-title":"Haemophilia"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"559","DOI":"10.2147\/JBM.S371438","article-title":"Gene therapy and hemophilia: where do we go from here?","volume":"13","author":"N S Bolous","year":"2022","journal-title":"J Blood Med"},{"issue":"02","key":"ref92","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.drudis.2020.11.024","article-title":"Market access of gene therapies across Europe, USA, and Canada: challenges, trends, and solutions","volume":"26","author":"E van Overbeeke","year":"2021","journal-title":"Drug Discov Today"},{"issue":"S 04","key":"ref93","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/hae.14512","article-title":"Haemophilia gene therapy-Update on new country initiatives","volume":"28","author":"U M Reiss","year":"2022","journal-title":"Haemophilia"},{"issue":"10","key":"ref94","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1089\/hum.2018.137","article-title":"Preclinical development of a hematopoietic stem and progenitor cell bioengineered factor VIII lentiviral vector gene therapy for hemophilia A","volume":"29","author":"C B Doering","year":"2018","journal-title":"Hum Gene Ther"},{"issue":"S 01","key":"ref95","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1182\/blood-2023-188513","article-title":"Assessment of Transduction of CD34+ human hematopoietic stem cells from patients with severe hemophilia-A with lentiviral vector carrying a high expression FVIII Transgene (CD68\u2013ET3-LV)","volume":"142","author":"G Singh","year":"2023","journal-title":"Blood"},{"issue":"01","key":"ref96","doi-asserted-by":"crossref","first-page":"16838","DOI":"10.1038\/s41598-019-53198-y","article-title":"Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII","volume":"9","author":"H Chen","year":"2019","journal-title":"Sci Rep"},{"issue":"01","key":"ref97","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s13059-019-1907-9","article-title":"Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse","volume":"20","author":"J P Zhang","year":"2019","journal-title":"Genome Biol"},{"key":"ref98","doi-asserted-by":"crossref","first-page":"672564","DOI":"10.3389\/fcell.2021.672564","article-title":"CRISPR\/Cas9-mediated in vivo genetic correction in a mouse model of hemophilia A","volume":"9","author":"S Luo","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"09","key":"ref99","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1080\/14712598.2022.2090241","article-title":"Challenges and opportunities when transitioning from in vivo gene replacement to in vivo CRISPR\/Cas9 therapies - a spotlight on hemophilia","volume":"22","author":"O G Segurado","year":"2022","journal-title":"Expert Opin Biol Ther"},{"key":"ref100","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1089\/hum.2023.112","article-title":"Hemophilia gene therapy: the end of the beginning?","volume":"34","author":"D De Wolf","year":"2023","journal-title":"Hum Gene Ther"}],"container-title":["Seminars in Thrombosis and Hemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/s-0044-1785483.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T23:37:14Z","timestamp":1737502634000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/s-0044-1785483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,8]]},"references-count":88,"journal-issue":{"issue":"01","published-online":{"date-parts":[[2025,1,21]]},"published-print":{"date-parts":[[2025,2]]}},"URL":"https:\/\/doi.org\/10.1055\/s-0044-1785483","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0094-6176","1098-9064"],"issn-type":[{"value":"0094-6176","type":"print"},{"value":"1098-9064","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,8]]}}}