Skip to content
2000
image of A Paradigm Shift in Hemophilia Care: The Promise of Gene Therapy

Abstract

Introduction

The discovery of the gene as the primary unit of inheritance marked the beginning of intensive research into targeted genome modifications for treating rare genetic diseases. Despite conventional approaches such as continuous factor replacement or novel non-factor therapies, the need for a one-time infusion and long-term sustenance of clotting factors is evident. This review focuses on gene therapies discovered to treat patients with hemophilia. This narrative review seeks to highlight the current potential of gene therapies for hemophilia, elucidate their mode of action, and assess their long-term effectiveness and clinical significance.

Methods

A literature search in PubMed, Embase, Google Scholar, and Scopus databases was done using search terms like gene therapy, viral vectors, Roctavian, hemophilia, etranacogene dezaparvovec, AAV, and FIX-Padua variant.

Results

Following intensive clinical trials and successful outcomes, the currently available FDA-approved gene therapies include valoctocogene roxaparvovec (Roctavian) for hemophilia A and etranacogene dezaparvovec (Hemgenix), and fidanacogene elaparvovec (Beqvez) for hemophilia B, and an antibody-based therapy, Marstacimab (Hympavzi) for both hemophilia A and B.

Discussion

Decades of clinical research on introducing gene therapy as a potential therapy for hemophilia A and B have paved the way for successful discovery to overcome the long-term burden of factor replacement and other adjunct therapies. Gene therapy has shown persistent success in hemophilia, with clinical trials demonstrating long-term expression of functional clotting factors (Factor VIII or IX). This has reduced bleeding episodes remarkably and the need for regular factor replacement therapy. Yet the drugs need to be studied further to assess long term safety and efficacy following administration.

Conclusions

Gene therapy has shown new possibilities in hemophilia, with many patients achieving near-normal levels of clotting factors and experiencing a significant reduction in bleeding episodes. However, challenges remain, including potential declines in Factor VIII levels over time, immune responses to viral vectors, and high treatment costs. Ongoing research is focused on improving durability, expanding eligibility, and exploring alternative delivery methods.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cgt/10.2174/0115665232389378250727013548
2025-08-07
2025-09-13

  • From This Site

    /content/journals/cgt/10.2174/0115665232389378250727013548
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Blanchette V.S. Key N.S. Ljung L.R. Manco-Johnson M.J. van den Berg H.M. Srivastava A. Definitions in hemophilia: Communication from the SSC of the ISTH. J. Thromb. Haemost. 2014 12 11 1935 1939 10.1111/jth.12672 25059285
    [Google Scholar]
  2. Mehta P. Reddivari A.K.R. Hemophilia. In: StatPearls. Treasure Island, FL StatPearls Publishing 2024
    [Google Scholar]
  3. Lewandowska M.D. Connors J.M. Factor X.I. Factor XI deficiency. Hematol. Oncol. Clin. North Am. 2021 35 6 1157 1169 10.1016/j.hoc.2021.07.012 34535287
    [Google Scholar]
  4. Zimmerman B. Valentino L.A. Hemophilia: In review. Pediatr. Rev. 2013 34 7 289 295 10.1542/pir.34.7.289 23818083
    [Google Scholar]
  5. Coffin D. Gouider E. Konkle B. Hermans C. Lambert C. Diop S. Ayoub E. Tootoonchian E. Youttananukorn T. Dakik P. Pereira T. Iorio A. Pierce G.F. Abdel Mohsen M. Adeyemo T. Ai Sim G. Al-Rahal N. Alexis C. Ali T. Awodu O. Aysarieva B. Aziz A. Barsallo N. Biswas A. Blair A. Blatny J. Borhany M. Castillo D. Catarino C. Chuansumrit A. Coetzee M. Darwish Mohamad Ibrahim A. Diop S. Djenouni A. El Ekiaby A. El Khorassani M. Fawcett K. Ganieva A. Govindan S. Gwarzo D. Hailemariam S. Harper P. Hassan T. Hassan M. Hermans C. Hernandez F. Imran A. John J. Keikhaei B. Kotila T. Liam C. Marhaeni W. Mbanya D. Mekjarusgul P. Meknassi N. Micic D. Mlombe Y. Motusheva R. Munube D. Nagao A. Najmi S. Narayana Pillai V. Narbekov T. Nasution D. Natesirinilkul R. Nchimba L. N’dogomo M. Neme D. Nguyen P. Nguyen H. Nguyen Thi M. Nigam R. Njuguna F. Nwagha T. Obeida A. Owusu-Ofori S. Palascak J. Pellegrini G. Philip C. Ping C. Poudyal B. Rabbani G. Rakoto Alson O. Razali H. Ruchutrakul T. Ruiz-Saez A. Saengboon S. Salhi N. Satti M. See Guan T. Shah S. Shikuku T. Si Yuan N. Sidarthan N. Siew Looi T. Songthawee N. Sosothikul D. Surapolchai P. Suryani S. Syakira N. Thevarajah A. Tzong T. Udo C. Wong L. Yuguda S. Zafar T. Zaman Miah M. World Bleeding Disorders Registry Participating Investigators The world federation of hemophilia world bleeding disorders registry: Insights from the first 10,000 patients. Res. Pract. Thromb. Haemost. 2023 7 8 102264 10.1016/j.rpth.2023.102264 38193052
    [Google Scholar]
  6. Hassan S. Monahan R.C. Mauser-Bunschoten E.P. van Vulpen L.F.D. Eikenboom J. Beckers E.A.M. Hooimeijer L. Ypma P.F. Nieuwenhuizen L. Coppens M. Schols S.E.M. Leebeek F.W.G. Smit C. Driessens M.H. le Cessie S. van Balen E.C. Rosendaal F.R. van der Bom J.G. Gouw S.C. Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001–2018. J. Thromb. Haemost. 2021 19 3 645 653 10.1111/jth.15182 33217158
    [Google Scholar]
  7. Skjefstad K. Solberg O. Glosli H. von der Lippe C. Feragen K.B. Life expectancy and cause of death in individuals with haemophilia A and B in Norway, 1986‐2018. Eur. J. Haematol. 2020 105 5 608 615 10.1111/ejh.13494 32710483
    [Google Scholar]
  8. Castaman G. Matino D. Hemophilia A and B: Molecular and clinical similarities and differences. Haematologica 2019 104 9 1702 1709 10.3324/haematol.2019.221093 31399527
    [Google Scholar]
  9. Pshenichnikova O. Salomashkina V. Poznyakova J. Selivanova D. Chernetskaya D. Yakovleva E. Dimitrieva O. Likhacheva E. Perina F. Zozulya N. Surin V. Spectrum of causative mutations in patients with hemophilia a in Russia. Genes 2023 14 2 260 10.3390/genes14020260 36833187
    [Google Scholar]
  10. Bagnall R.D. Waseem N. Green P.M. Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002 99 1 168 174 10.1182/blood.V99.1.168 11756167
    [Google Scholar]
  11. Tantawy A.A.G. Molecular genetics of hemophilia A: Clinical perspectives. Egypt. J. Med. Hum. Genet. 2010 11 2 105 114 10.1016/j.ejmhg.2010.10.005
    [Google Scholar]
  12. Xue F. Zhang L. Sui T. Ge J. Gu D. Du W. Zhao H. Yang R. Factor VIII gene mutations profile in 148 Chinese hemophilia A subjects. Eur. J. Haematol. 2010 85 3 264 272 10.1111/j.1600‑0609.2010.01481.x 20528906
    [Google Scholar]
  13. Thompson A.R. Structure and function of the factor VIII gene and protein. Semin. Thromb. Hemost. 2003 29 1 011 022 10.1055/s‑2003‑37935 12640560
    [Google Scholar]
  14. Sarmiento Doncel S. Díaz Mosquera G.A. Cortes J.M. Agudelo Rico C. Meza Cadavid F.J. Peláez R.G. Haemophilia A. Haemophilia A: A review of clinical manifestations, treatment, mutations, and the development of inhibitors. Hematol. Rep. 2023 15 1 130 150 10.3390/hematolrep15010014 36810557
    [Google Scholar]
  15. Ward N.J. Buckley S.M.K. Waddington S.N. VandenDriessche T. Chuah M.K.L. Nathwani A.C. McIntosh J. Tuddenham E.G.D. Kinnon C. Thrasher A.J. McVey J.H. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 2011 117 3 798 807 10.1182/blood‑2010‑05‑282707 21041718
    [Google Scholar]
  16. Miller C.H. The clinical genetics of hemophilia B (factor IX deficiency). Appl. Clin. Genet. 2021 14 445 454 10.2147/TACG.S288256 34848993
    [Google Scholar]
  17. Shen G. Gao M. Cao Q. Li W. The molecular basis of FIX deficiency in hemophilia B. Int. J. Mol. Sci. 2022 23 5 2762 10.3390/ijms23052762 35269902
    [Google Scholar]
  18. Arruda V.R. Hagstrom J.N. Deitch J. Heiman-Patterson T. Camire R.M. Chu K. Fields P.A. Herzog R.W. Couto L.B. Larson P.J. High K.A. Posttranslational modifications of recombinant myotube-synthesized human factor IX. Blood 2001 97 1 130 138 10.1182/blood.V97.1.130 11133752
    [Google Scholar]
  19. Biology and normal function of factor VIII and factor IX. 2023 Available from: https://www.uptodate.com/contents/biology-and-normal-function-of-factor-viii-and-factor-ix/print
  20. Kah Yuen L. Zakaria Z. Mat Yusoff Y. A novel missense mutation of F 9 gene in hemophilia B patients. J. Blood Disord. Transfus. 2017 8 3 10.4172/2155‑9864.1000383
    [Google Scholar]
  21. Thachil J. Connors J.M. Mahlangu J. Sholzberg M. Reclassifying hemophilia to include the definition of outcomes and phenotype as new targets. J. Thromb. Haemost. 2023 21 7 1737 1740 10.1016/j.jtha.2023.03.016 36972786
    [Google Scholar]
  22. Coppola A. Di Capua M. Di Minno M.N.D. Di Palo M. Marrone E. Ieranò P. Arturo C. Tufano A. Cerbone A.M. Treatment of hemophilia: A review of current advances and ongoing issues. J. Blood Med. 2010 1 183 195 10.2147/JBM.S6885 22282697
    [Google Scholar]
  23. Srivastava A. Brewer A.K. Mauser-Bunschoten E.P. Key N.S. Kitchen S. Llinas A. Ludlam C.A. Mahlangu J.N. Mulder K. Poon M.C. Street A. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia Guidelines for the management of hemophilia. Haemophilia 2013 19 1 e1 e47 10.1111/j.1365‑2516.2012.02909.x 22776238
    [Google Scholar]
  24. Mansouritorghabeh H. Clinical and laboratory approaches to hemophilia a. Iran. J. Med. Sci. 2015 40 3 194 205 25999618
    [Google Scholar]
  25. Konkle B.A. Nakaya Fletcher S. Hemophilia A. GeneReviews®. Adam M.P. Feldman J. Mirzaa G.M. Pagon R.A. Wallace S.E. Amemiya A. editor [Internet] Seattle, WA University of Washington, Seattle 1993 [cited 2025 Aug 26]. Available from:http://www.ncbi.nlm.nih.gov/books/NBK1404/ 20301578
    [Google Scholar]
  26. Nathwani A.C. Gene therapy for hemophilia. Hematology 2022 2022 1 569 578 10.1182/hematology.2022000388 36485127
    [Google Scholar]
  27. Marchesini E. Morfini M. Valentino L. Recent advances in the treatment of hemophilia: A review. Biologics 2021 15 221 235 34163136
    [Google Scholar]
  28. Mannucci P.M. Ham-Wasserman Lecture. Hematology 2002 2002 1 1 9 10.1182/asheducation‑2002.1.1 12171771
    [Google Scholar]
  29. Franchini M. Mannucci P.M. The more recent history of hemophilia treatment. Semin. Thromb. Hemost. 2022 48 8 904 910 10.1055/s‑0042‑1756188 36108649
    [Google Scholar]
  30. Okaygoun D. Oliveira D.D. Soman S. Williams R. Advances in the management of haemophilia: Emerging treatments and their mechanisms. J. Biomed. Sci. 2021 28 1 64 10.1186/s12929‑021‑00760‑4 34521404
    [Google Scholar]
  31. Mahlangu J. Cerquiera M. Srivastava A. Emerging therapies for haemophilia ‐ Global perspective. Haemophilia 2018 24 S6 Suppl. 6 15 21 10.1111/hae.13510 29878661
    [Google Scholar]
  32. Mannucci P.M. Use of desmopressin in the treatment of hemophilia A: Towards a golden jubilee. Haematologica 2018 103 3 379 381 10.3324/haematol.2018.187567 29491128
    [Google Scholar]
  33. Richardson D.W. Robinson A.G. Desmopressin. Ann. Intern. Med. 1985 103 2 228 239 10.7326/0003‑4819‑103‑2‑228 3893256
    [Google Scholar]
  34. Romano L.G.R. van Vulpen L.F.D. den Exter P.L. Heubel-Moenen F.C.J.I. Hooijmeijer H.L. Coppens M. Fijnvandraat K. Schols S.E.M. Ypma P.F. Smit C. Driessens M.H.E. Rosendaal F.R. van der Bom J.G. Gouw S.C. Kruip M.J.H.A. Desmopressin in nonsevere hemophilia A: patient perspectives on use and efficacy. Res. Pract. Thromb. Haemost. 2023 7 5 100281 10.1016/j.rpth.2023.100281 37601028
    [Google Scholar]
  35. Pabinger I. Fries D. Schöchl H. Streif W. Toller W. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien. Klin. Wochenschr. 2017 129 9-10 303 316 10.1007/s00508‑017‑1194‑y 28432428
    [Google Scholar]
  36. Vagrecha A. Stanco J. Origho M. Martinez L. Acharya S. Use of low dose tranexamic acid in patients with bleeding disorders. Blood 2024 144 Suppl. 1 1223 1223 10.1182/blood‑2024‑206074
    [Google Scholar]
  37. Parisi K. Kumar A. Emicizumab. StatPearls. Treasure Island, FL StatPearls Publishing 2024
    [Google Scholar]
  38. Alcedo Andrade P.E. Mannucci P.M. Kessler C.M. Emicizumab: The hemophilia A game-changer. Haematologica 2024 109 5 1334 1347 37916312
    [Google Scholar]
  39. Salwa Pasha S.F.A. Fatima WW Srinivasamurthy S.K. Gene therapies for spinal muscular atrophy and duchenne muscular dystrophy: A pathbreaking moment in therapeutics. J. Pharm. Res. Int. 2022 15 35 10.9734/jpri/2022/v34i53B7229
    [Google Scholar]
  40. Gonçalves G.A.R. Paiva R.M.A. Gene therapy: Advances, challenges and perspectives. Einstein 2017 15 3 369 375 10.1590/s1679‑45082017rb4024 29091160
    [Google Scholar]
  41. Leebeek FWG Miesbach W Gene therapy for hemophilia: A review on clinical benefit, limitations, and remaining issues. Blood 2021 138 11 923 931 10.1182/blood.2019003777
    [Google Scholar]
  42. Rajapaksha I. Angus P. Herath C. Rajapaksha I. Angus P. Herath C. Adeno-associated virus (AAV)-mediated gene therapy for disorders of inherited and non-inherited origin. In: In vivo and ex vivo gene therapy for inherited and non-inherited disorders. IntechOpen IntechOpen 2018 126 24
    [Google Scholar]
  43. Manno C.S. Pierce G.F. Arruda V.R. Glader B. Ragni M. Rasko J.J.E. Ozelo M.C. Hoots K. Blatt P. Konkle B. Dake M. Kaye R. Razavi M. Zajko A. Zehnder J. Rustagi P. Nakai H. Chew A. Leonard D. Wright J.F. Lessard R.R. Sommer J.M. Tigges M. Sabatino D. Luk A. Jiang H. Mingozzi F. Couto L. Ertl H.C. High K.A. Kay M.A. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 2006 12 3 342 347 10.1038/nm1358 16474400
    [Google Scholar]
  44. Ohmori T. Mizukami H. Ozawa K. Sakata Y. Nishimura S. New approaches to gene and cell therapy for hemophilia. J. Thromb. Haemost. 2015 13 S133 S142 10.1111/jth.12926 26149014
    [Google Scholar]
  45. Monahan P.E. Gene therapy in an era of emerging treatment options for hemophilia B. J Thromb Haemost 2015 13 Suppl 1 S151 S160 10.1111/jth.12957
    [Google Scholar]
  46. Naso M.F. Tomkowicz B. Perry W.L. Strohl W.R. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 2017 31 4 317 334 10.1007/s40259‑017‑0234‑5 28669112
    [Google Scholar]
  47. Berns K.I. Flotte T.R. Gene therapy: Use of viruses as vectors. Encyclopedia of Virology. 3rd ed Mahy B.W.J. Van Regenmortel M.H.V. Oxford Academic Press 2008 301 306 [Internet 10.1016/B978‑012374410‑4.00554‑9
    [Google Scholar]
  48. Cevher E. Sezer A.D. Çağlar E.Ş. Cevher E. Sezer A.D. Çağlar E.Ş. Gene delivery systems: Recent progress in viral and non-viral therapy. In: Recent Advances in Novel Drug Carrier Systems InTech 2012 31 437 70 10.5772/53392
    [Google Scholar]
  49. Navarro-Oliveros M. Vidaurrazaga A. Soares Guerra G. Castellana D. Embade N. Millet O. Marigorta U.M. Abrescia N.G.A. Seroprevalence of adeno-associated virus types 1, 2, 3, 4, 5, 6, 8, and 9 in a Basque cohort of healthy donors. Sci. Rep. 2024 14 1 15941 10.1038/s41598‑024‑66546‑4 38987633
    [Google Scholar]
  50. Zhao L. Yang Z. Zheng M. Shi L. Gu M. Liu G. Miao F. Chang Y. Huang F. Tang N. Recombinant adeno-associated virus 8 vector in gene therapy: Opportunities and challenges. Genes Dis. 2024 11 1 283 293 10.1016/j.gendis.2023.02.010 37588223
    [Google Scholar]
  51. Sierra-Delgado J.A. Likhite S. Bautista P.K. Gómez-Ochoa S.A. Echeverría L.E. Guío E. Vargas C. Serrano N.C. Meyer K.C. Rincon M.Y. Prevalence of neutralizing antibodies against adeno-associated virus serotypes 1, 2, and 9 in non-injected latin american patients with heart failure—anvias study. Int. J. Mol. Sci. 2023 24 6 5579 10.3390/ijms24065579 36982654
    [Google Scholar]
  52. Rangarajan S. Walsh L. Lester W. Perry D. Madan B. Laffan M. Yu H. Vettermann C. Pierce G.F. Wong W.Y. Pasi K.J. aav5–factor VIII gene transfer in severe hemophilia A. N. Engl. J. Med. 2017 377 26 2519 2530 10.1056/NEJMoa1708483 29224506
    [Google Scholar]
  53. FDA approves first gene therapy for adults with severe hemophilia A. 2024 Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-adults-severe-hemophilia
  54. First Gene Therapy for Adults with Severe Hemophilia A, BioMarin’s ROCTAVIANTM (valoctocogene roxaparvovec), Approved by European Commission (EC) [Internet]. [cited 2025 Aug 26]. Available from: https://investors.biomarin.com/news/news-details/2022/First-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A-BioMarins-ROCTAVIAN-valoctocogene-roxaparvovec-Approved-by-European-Commission-EC-08-24-2022/
  55. Pasi K.J. Rangarajan S. Mitchell N. Lester W. Symington E. Madan B. Laffan M. Russell C.B. Li M. Pierce G.F. Wong W.Y. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N. Engl. J. Med. 2020 382 1 29 40 10.1056/NEJMoa1908490 31893514
    [Google Scholar]
  56. Ozelo M.C. Mahlangu J. Pasi K.J. Giermasz A. Leavitt A.D. Laffan M. Symington E. Quon D.V. Wang J.D. Peerlinck K. Pipe S.W. Madan B. Key N.S. Pierce G.F. O’Mahony B. Kaczmarek R. Henshaw J. Lawal A. Jayaram K. Huang M. Yang X. Wong W.Y. Kim B. GENEr8-1 Trial Group Valoctocogene roxaparvovec gene therapy for hemophilia A. N. Engl. J. Med. 2022 386 11 1013 1025 10.1056/NEJMoa2113708 35294811
    [Google Scholar]
  57. Mahlangu J. Kaczmarek R. von Drygalski A. Shapiro S. Chou S.C. Ozelo M.C. Kenet G. Peyvandi F. Wang M. Madan B. Key N.S. Laffan M. Dunn A.L. Mason J. Quon D.V. Symington E. Leavitt A.D. Oldenburg J. Chambost H. Reding M.T. Jayaram K. Yu H. Mahajan R. Chavele K.M. Reddy D.B. Henshaw J. Robinson T.M. Wong W.Y. Pipe S.W. GENEr8-1 Trial Group Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N. Engl. J. Med. 2023 388 8 694 705 10.1056/NEJMoa2211075 36812433
    [Google Scholar]
  58. VandenDriessche T. Chuah M.K. Hyperactive factor IX padua: A game-changer for hemophilia gene therapy. Mol. Ther. 2018 26 1 14 16 10.1016/j.ymthe.2017.12.007 29274719
    [Google Scholar]
  59. Thornburg C.D. Etranacogene dezaparvovec for hemophilia B gene therapy. Ther. Adv. Rare Dis. 2021 2 26330040211058896 10.1177/26330040211058896 37181105
    [Google Scholar]
  60. Anguela X.M. High K.A. Hemophilia B and gene therapy: A new chapter with etranacogene dezaparvovec. Blood Adv. 2024 8 7 1796 1803 10.1182/bloodadvances.2023010511 38592711
    [Google Scholar]
  61. Heo Y.A. Etranacogene dezaparvovec: First approval. Drugs 2023 83 4 347 352 10.1007/s40265‑023‑01845‑0 36802324
    [Google Scholar]
  62. Miesbach W. Meijer K. Coppens M. Kampmann P. Klamroth R. Schutgens R. Tangelder M. Castaman G. Schwäble J. Bonig H. Seifried E. Cattaneo F. Meyer C. Leebeek F.W.G. Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B. Blood 2018 131 9 1022 1031 10.1182/blood‑2017‑09‑804419 29246900
    [Google Scholar]
  63. Von Drygalski A. Giermasz A. Castaman G. Key N.S. Lattimore S. Leebeek F.W.G. Miesbach W. Recht M. Long A. Gut R. Sawyer E.K. Pipe S.W. Etranacogene dezaparvovec (AMT-061 phase 2b): Normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv. 2019 3 21 3241 3247 10.1182/bloodadvances.2019000811 31698454
    [Google Scholar]
  64. Coppens M. Pipe S.W. Miesbach W. Astermark J. Recht M. van der Valk P. Ewenstein B. Pinachyan K. Galante N. Le Quellec S. Monahan P.E. Leebeek F.W.G. Castaman G. Crary S.E. Escobar M. Gomez E. Haley K.M. Hermans C.R.J.R. Kampmann P. Kazmi R. Key N.S. Klamroth R. Konkle B.A. Kruse-Jarres R. Lattimore S. Lemons R. Meijer K. O’Connell N. Quon D.V. Raheja P. Symington E. Verhamme P. Visweshwar N. von Drygalski A. Wang M. Wheeler A.P. White S. Young G. HOPE-B Investigators Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial. Lancet Haematol. 2024 11 4 e265 e275 10.1016/S2352‑3026(24)00006‑1 38437857
    [Google Scholar]
  65. Pipe S.W. Leebeek F.W.G. Recht M. Key N.S. Castaman G. Miesbach W. Lattimore S. Peerlinck K. Van der Valk P. Coppens M. Kampmann P. Meijer K. O’Connell N. Pasi K.J. Hart D.P. Kazmi R. Astermark J. Hermans C.R.J.R. Klamroth R. Lemons R. Visweshwar N. von Drygalski A. Young G. Crary S.E. Escobar M. Gomez E. Kruse-Jarres R. Quon D.V. Symington E. Wang M. Wheeler A.P. Gut R. Liu Y.P. Dolmetsch R.E. Cooper D.L. Li Y. Goldstein B. Monahan P.E. Gene therapy with etranacogene dezaparvovec for hemophilia B. N. Engl. J. Med. 2023 388 8 706 718 10.1056/NEJMoa2211644 36812434
    [Google Scholar]
  66. U.S. FDA Approves Pfizer’s BEQVEZTM (fidanacogene elaparvovec- dzkt), a One-Time Gene Therapy for Adults with Hemophilia B | Pfizer [Internet]. [cited 2025 Aug 26]. Available from: https://www.pfizer.com/news/press-release/press-release-detail/usfda-approves-pfizers-beqveztm-fidanacogene-elaparvovec
  67. New gene therapy treatment for haemophilia B. 2024 Available from: https://www.ema.europa.eu/en/news/new-gene-therapy-treatment-haemophilia-b
  68. Cuker A. Kavakli K. Frenzel L. Wang J.D. Astermark J. Cerqueira M.H. Iorio A. Katsarou-Fasouli O. Klamroth R. Shapiro A.D. Hermans C. Ishiguro A. Leavitt A.D. Oldenburg J.B. Ozelo M.C. Teitel J. Biondo F. Fang A. Fuiman J. McKay J. Sun P. Rasko J.E.J. Rupon J. BENEGENE-2 Trial Investigators Gene therapy with fidanacogene elaparvovec in adults with hemophilia B. N. Engl. J. Med. 2024 391 12 1108 1118 10.1056/NEJMoa2302982 39321362
    [Google Scholar]
  69. Park S. Park J.K. Back to basics: The coagulation pathway. Blood Res. 2024 59 1 35 10.1007/s44313‑024‑00040‑8 39466528
    [Google Scholar]
  70. Chowdary P. Anti-tissue factor pathway inhibitor (TFPI) therapy: A novel approach to the treatment of haemophilia. Int. J. Hematol. 2020 111 1 42 50 10.1007/s12185‑018‑2548‑6 30302740
    [Google Scholar]
  71. Kato H. Tissue factor pathway inhibitor: structure and function. Recent Advances in Thrombosis and Hemostasis 2008. Tanaka K. Davie E.W. Ikeda Y. Iwanaga S. Saito H. Sueishi K. Tokyo Springer Japan 2008 147 161 10.1007/978‑4‑431‑78847‑8_8
    [Google Scholar]
  72. Mast A.E. Ruf W. Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy. J. Thromb. Haemost. 2022 20 6 1290 1300 10.1111/jth.15697 35279938
    [Google Scholar]
  73. Levin-Epstein M. FDA approves new treatment for hemophilia A or B. J Clin Eng 2025 50 1 2 Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hemophilia-or-b
    [Google Scholar]
  74. Mahlangu J. Lamas JL Morales JC Malan D.R. Teeter J. Charnigo R.J. Hwang E. Arkin S. Long‐term safety and efficacy of the anti‐tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results. Br. J. Haematol. 2023 200 2 240 248 Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.18495 10.1111/bjh.18495 36220152
    [Google Scholar]
  75. Pfizer. An Open-Label Study in Adolescent and Adult Severe (Coagulation Factor Activity <1%) Hemophilia A Participants With or Without Inhibitors or Moderately Severe to Severe Hemophilia B Participants (Coagulation Factor Activity ≤2%) With or Without Inhibitors Comparing Standard Treatment to PF- 06741086 Prophylaxis [Internet]. clinicaltrials.gov; 2025 Jun [cited 2025 Aug 26]. Report No.: NCT03938792. Available From:https://clinicaltrials.gov/study/NCT03938792
    [Google Scholar]
  76. Symington E. Rangarajan S. Lester W. Madan B. Pierce G.F. Raheja P. Millar C. Osmond D. Li M. Robinson T.M. Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A. Haemophilia 2024 30 5 1138 1147 10.1111/hae.15071 38975624
    [Google Scholar]
  77. Leebeek F.W.G. Meijer K. Coppens M. Kampmann P. Klamroth R. Schutgens R. Castaman G. Seifried E. Schwaeble J. Bönig H. Sawyer E.K. Miesbach W.A. AMT-060 gene therapy in adults with severe or moderate-severe hemophilia b confirm stable fix expression and durable reductions in bleeding and factor ix consumption for up to 5 years. Blood 2020 136 26 Suppl. 1 10.1182/blood‑2020‑139225
    [Google Scholar]
  78. A gene therapy study for hemophilia B. Patent NCT02484092 2020
  79. Matino D. Acharya S. Palladino A. Hwang E. McDonald R. Taylor C.T. Teeter J. Efficacy and safety of the anti-tissue factor pathway inhibitor marstacimab in participants with severe hemophilia without inhibitors: Results from the phase 3 basis trial. Blood 2023 142 285 Suppl. 1 10.1182/blood‑2023‑181263
    [Google Scholar]
  80. Mingozzi F. Anguela X.M. Pavani G. Chen Y. Davidson R.J. Hui D.J. Yazicioglu M. Elkouby L. Hinderer C.J. Faella A. Howard C. Tai A. Podsakoff G.M. Zhou S. Basner-Tschakarjan E. Wright J.F. High K.A. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl. Med. 2013 5 194 194ra92 10.1126/scitranslmed.3005795 23863832
    [Google Scholar]
  81. Earley J. Piletska E. Ronzitti G. Piletsky S. Evading and overcoming AAV neutralization in gene therapy. Trends Biotechnol. 2023 41 6 836 845 10.1016/j.tibtech.2022.11.006 36503641
    [Google Scholar]
  82. Potter R.A. Peterson E.L. Griffin D. Cooper Olson G. Lewis S. Cochran K. Mendell J.R. Rodino-Klapac L.R. Use of plasmapheresis to lower anti-AAV antibodies in nonhuman primates with pre-existing immunity to AAVrh74. Mol. Ther. Methods Clin. Dev. 2024 32 1 101195 10.1016/j.omtm.2024.101195 38327805
    [Google Scholar]
  83. Klamroth R. Hayes G. Andreeva T. Gregg K. Suzuki T. Mitha I.H. Hardesty B. Shima M. Pollock T. Slev P. Oldenburg J. Ozelo M.C. Stieltjes N. Castet S.M. Mahlangu J. Peyvandi F. Kazmi R. Schved J.F. Leavitt A.D. Callaghan M. Pan-Petesch B. Quon D.V. Andrews J. Trinh A. Li M. Wong W.Y. Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A. Hum. Gene Ther. 2022 33 7-8 432 441 10.1089/hum.2021.287 35156839
    [Google Scholar]
  84. Boutin S. Monteilhet V. Veron P. Leborgne C. Benveniste O. Montus M.F. Masurier C. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum. Gene Ther. 2010 21 6 704 712 10.1089/hum.2009.182 20095819
    [Google Scholar]
  85. Calcedo R. Vandenberghe L.H. Gao G. Lin J. Wilson J.M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 2009 199 3 381 390 10.1086/595830 19133809
    [Google Scholar]
  86. Majowicz A. Nijmeijer B. Lampen M.H. Spronck L. de Haan M. Petry H. van Deventer S.J. Meyer C. Tangelder M. Ferreira V. Therapeutic hFIX activity achieved after single AAV5-hFIX treatment in hemophilia B patients and NHPs with pre-existing Anti-AAV5 NABs. Mol. Ther. Methods Clin. Dev. 2019 14 27 36 10.1016/j.omtm.2019.05.009 31276009
    [Google Scholar]
  87. Mingozzi F. High K.A. Immune responses to AAV vectors: Overcoming barriers to successful gene therapy. Blood 2013 122 1 23 36 10.1182/blood‑2013‑01‑306647 23596044
    [Google Scholar]
  88. Yasir M. Goyal A. Sonthalia S. Corticosteroid adverse effects. In: StatPearls. Treasure Island, FL StatPearls Publishing 2024
    [Google Scholar]
  89. Schultz B.R. Chamberlain J.S. Recombinant adeno-associated virus transduction and integration. Mol. Ther. 2008 16 7 1189 1199 10.1038/mt.2008.103 18500252
    [Google Scholar]
  90. Liver Safety Case Report From the Phase 3 HOPE-B Gene Therapy Trial in Adults With Hemophilia B [Internet]. [cited 2025 Aug 26]. Available from: https://genetherapy.isth.org/liver-safety-case-report-from-the-phase-3-hope-b-gene-therapy-trial-in-adults-with-hemophilia-b
  91. Inc uniQure. GlobeNewswire News Room. 2021 [cited 2025 Aug 26]. uniQure Announces Findings from Reported Case of Hepatocellular Carcinoma (HCC) in Hemophilia B Gene Therapy Program. Available from: https://www.globenewswire.com/news-release/2021/03/29/2200653/0/en/uniQure-Announces-Findings-from-Reported-Case-of-Hepatocellular-Carcinoma-HCC-in-Hemophilia-B-Gene-Therapy-Program.html
  92. Ma Y. Zhang L. Huang X. Genome modification by CRISPR/Cas9. FEBS J. 2014 281 23 5186 5193 10.1111/febs.13110 25315507
    [Google Scholar]
  93. Wang L. Yang Y. Breton C.A. White J. Zhang J. Che Y. Saveliev A. McMenamin D. He Z. Latshaw C. Li M. Wilson J.M. CRISPR/Cas9-mediated in vivo gene targeting corrects hemostasis in newborn and adult factor IX–knockout mice. Blood 2019 133 26 2745 2752 10.1182/blood.2019000790 30975639
    [Google Scholar]
  94. Thornburg C.D. Simmons D.H. von Drygalski A. Evaluating gene therapy as a potential paradigm shift in treating severe hemophilia. BioDrugs 2023 37 5 595 606 10.1007/s40259‑023‑00615‑4 37490225
    [Google Scholar]
  95. Machin N. Ragni M.V. Smith K.J. Gene therapy in hemophilia A: A cost-effectiveness analysis. Blood Adv. 2018 2 14 1792 1798 10.1182/bloodadvances.2018021345 30042145
    [Google Scholar]
  96. Biomarin announces agreement with german health insurance fund on reimbursement amount for ROCTAVIAN® (valoctocogene roxaparvovec-rvox) for severe hemophilia A in Germany. 2023 Available from: https://investors.biomarin.com/news/news-details/2023/BioMarin-Announces-Agreement-with-German-Health-Insurance-Fund-on-Reimbursement-Amount-for-ROCTAVIAN-valoctocogene-roxaparvovec-rvox-for-Severe-Hemophilia-A-in-Germany-11-28-2023/default.aspx
  97. Pfizer's Hympavzi Approved at $795,600, Disrupts Hemophilia Market. [Internet]. [cited 2025 Aug 26] Available from: https://synapse.patsnap.com/article/pfizers-hympavzi-approved-at-795600-disrupts-hemophilia-market
  98. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Italy. [Internet]. [cited 2025 Aug 26]. Available from: https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
  99. CSL behring announces positive reimbursement decision in Canada for HEMGENIX® (etranacogene dezaparvovec), the first gene therapy for hemophilia B. 2024 Available from: https://www.cslbehring.ca/news/2024/hemgenix
  100. Pfizer halts hemophilia B gene therapy. 2025 Available from: https://www.bleeding.org/news/pfizer-discontinues-beqvez-hemophilia-b-gene-therapy
/content/journals/cgt/10.2174/0115665232389378250727013548
Loading
A Paradigm Shift in Hemophilia Care: The Promise of Gene Therapy
Bentham Science Publishers ; https://doi.org/10.2174/0115665232389378250727013548
/content/journals/cgt/10.2174/0115665232389378250727013548
/content/journals/cgt/10.2174/0115665232389378250727013548
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: AAV vectors ; hemophilia A ; clotting factor ; hemostasis ; bleeding disorder ; Gene therapy ; hemophilia B ; etranacogene dezaparvovec ; valoctocogene roxaparvovec

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test