Skip to content
2000
image of Advances in Gene Therapy Clinical Trials for Hemophilia Care

Abstract

Gene therapy has revolutionized the therapeutic landscape for hemophilia A and B, offering the potential for sustained endogenous production of coagulation factors VIII and IX. Recent advances in adeno-associated virus (AAV)-mediated gene transfer, particularly the approvals of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparvovec (Hemgenix), represent significant milestones in hemophilia care. This mini-review synthesizes emerging clinical data from phase I–III trials published between 2022 and 2025, emphasizing efficacy, durability, and immunogenicity profiles of leading AAV-based therapies. Innovations in vector design, such as liver-specific promoters, codon-optimized constructs, and novel capsids (., AAVhu37, AAVrh10, AAV-Spark100), have improved transgene expression and expanded eligibility. Despite notable success, challenges persist, including immune-mediated transaminitis, declining factor activity over time, particularly in hemophilia A, and limitations posed by preexisting neutralizing antibodies. Additionally, CRISPR-Cas9 and non-viral delivery systems are emerging as complementary strategies, potentially enhancing therapeutic precision and overcoming AAV-related barriers. The minireview also addresses the critical need for equitable access and scalable production models to ensure global availability of gene therapies. With ongoing innovation and multidisciplinary collaboration, gene therapy is poised to transition from experimental intervention to mainstream curative care in hemophilia and other hematologic diseases.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cgt/10.2174/0115665232413510250904105956
2025-09-05
2025-12-15

  • From This Site

    /content/journals/cgt/10.2174/0115665232413510250904105956
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. 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]
  2. Nathwani A.C. Gene therapy for hemophilia. Hematology (Am. Soc. Hematol. Educ. Program) 2022 2022 1 569 578 10.1182/hematology.2022000388 36485127
    [Google Scholar]
  3. Iorio A. Stonebraker J.S. Chambost H. Establishing the prevalence and prevalence at birth of hemophilia in Males. Ann. Intern. Med. 2019 171 8 540 546 10.7326/M19‑1208 31499529
    [Google Scholar]
  4. George L.A. Hemophilia gene therapy comes of age. Blood Adv. 2017 1 26 2591 2599 10.1182/bloodadvances.2017009878 29296912
    [Google Scholar]
  5. Pipe S.W. Leebeek F.W.G. Recht M. Gene therapy with etranacogene dezaparvovec for Hemophilia B. N. Engl. J. Med. 2023 388 8 706 718 10.1056/NEJMoa2211644 36812434
    [Google Scholar]
  6. Ozelo M.C. Mahlangu J. Pasi K.J. Valoctocogene roxaparvovec gene therapy for hemophilia A. N. Engl. J. Med. 2022 386 11 1013 1025 10.1056/NEJMoa2113708 35294811
    [Google Scholar]
  7. George L.A. Monahan P.E. Eyster M.E. Multiyear Factor VIII expression after AAV gene transfer for Hemophilia A. N. Engl. J. Med. 2021 385 21 1961 1973 10.1056/NEJMoa2104205 34788507
    [Google Scholar]
  8. Pasi K.J. Rangarajan S. Mitchell N. 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]
  9. Quon D.V. Wang J.D. Wang M. Outcomes and management of invasive procedures in participants with Hemophilia A post gene therapy: A post hoc analysis of the GENEr8-1 phase III trial. Ther. Adv. Hematol. 2024 15 20406207241304645 10.1177/20406207241304645 39712873
    [Google Scholar]
  10. Simioni P. Tormene D. Tognin G. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N. Engl. J. Med. 2009 361 17 1671 1675 10.1056/NEJMoa0904377 19846852
    [Google Scholar]
  11. High K.A. Adeno-associated virus-mediated gene transfer for hemophilia B. Int. J. Hematol. 2002 76 4 310 318 10.1007/BF02982689 12463593
    [Google Scholar]
  12. Chowdary P. Shapiro S. Makris M. Phase 1–2 Trial of AAVS3 gene therapy in patients with hemophilia B. N. Engl. J. Med. 2022 387 3 237 247 10.1056/NEJMoa2119913 35857660
    [Google Scholar]
  13. Konkle B.A. Peyvandi F. Foster G.R. Corticosteroid use to mitigate transaminitis-associated decline in FVIII levels following valoctocogene roxaparvovec gene therapy: clinical practice guidance. J. Thromb. Haemost. 2025 23 7 2086 2094 10.1016/j.jtha.2025.02.042 40090623
    [Google Scholar]
  14. Ronzitti G. Gross D.A. Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors. Front. Immunol. 2020 11 670 10.3389/fimmu.2020.00670 32362898
    [Google Scholar]
  15. Dhungel B.P. Winburn I. Pereira C.F. Huang K. Chhabra A. Rasko J.E.J. Understanding AAV vector immunogenicity: From particle to patient. Theranostics 2024 14 3 1260 1288 10.7150/thno.89380 38323309
    [Google Scholar]
  16. Nguyen G.N. Everett J.K. Kafle S. A long-term study of AAV gene therapy in dogs with Hemophilia A identifies clonal expansions of transduced liver cells. Nat. Biotechnol. 2021 39 1 47 55 10.1038/s41587‑020‑0741‑7 33199875
    [Google Scholar]
  17. Morishige S. Mizuno S. Ozawa H. CRISPR/Cas9-mediated gene correction in Hemophilia B patient-derived iPSCs. Int. J. Hematol. 2020 111 2 225 233 10.1007/s12185‑019‑02765‑0 31664646
    [Google Scholar]
  18. Wang L. Smith J. Breton C. Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol. Nat. Biotechnol. 2018 36 8 717 725 10.1038/nbt.4182 29985478
    [Google Scholar]
  19. Psatha N. Paschoudi K. Papadopoulou A. Yannaki E. In vivo hematopoietic stem cell genome editing: Perspectives and limitations. Genes 2022 13 12 2222 10.3390/genes13122222 36553489
    [Google Scholar]
  20. George L.A. Fogarty P.F. Gene therapy for hemophilia: Past, present and future. Semin. Hematol. 2016 53 1 46 54 10.1053/j.seminhematol.2015.10.002 26805907
    [Google Scholar]
  21. Hussain M.S. Maqbool M. Arab M.M. Transforming hemophilia management: Lessons from gene therapy clinical trials. Mol. Biotechnol. 2025 1 2 10.1007/s12033‑025‑01464‑y 40586829
    [Google Scholar]
  22. Rangarajan S. Walsh L. Lester W. AAV5–Factor VIII gene transfer in severe hemophilia A. N. Engl. J. Med. 2017 377 26 2519 2530 10.1056/NEJMoa1708483 29224506
    [Google Scholar]
  23. Herzog R.W. Kaczmarek R. High K.A. Gene therapy for hemophilia – from basic science to first approvals of “one-and-done” therapies. Mol. Ther. 2025 33 5 2015 2034 10.1016/j.ymthe.2025.03.043 40156189
    [Google Scholar]
  24. Leavitt A.D. Konkle B.A. Stine K.C. Giroctocogene fitelparvovec gene therapy for severe Hemophilia A: 104-week analysis of the phase 1/2 Alta study. Blood 2024 143 9 796 806 10.1182/blood.2022018971 37871576
    [Google Scholar]
  25. Pipe SW Ferrante F Reis M First-in-human gene therapy study of AAVhu37 capsid vector technology in severe Hemophilia A-BAY 2599023 has broad patient eligibility and stable and sustained long-term expression of FVIII. Blood 2020 136 44 5.(Suppl. 1) 10.1182/blood‑2020‑139803
    [Google Scholar]
  26. Goodeve A.C. Hemophilia B. Molecular pathogenesis and mutation analysis. J. Thromb. Haemost. 2015 13 7 1184 1195 10.1111/jth.12958 25851415
    [Google Scholar]
  27. Nathwani AC Reiss U Tuddenham E Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing “empty viral particles” on safety and efficacy of gene transfer. Blood 2018 132 491.(Suppl. 1) 10.1182/blood‑2018‑99‑118334
    [Google Scholar]
  28. von Drygalski A. Gomez E. Giermasz A. Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years. Blood Adv. 2025 9 14 3543 3552 10.1182/bloodadvances.2024015291 40188458
    [Google Scholar]
  29. Pipe S. Poma A. Rajasekhar A. Gene therapy for hemophilia B: Results from the phase 1/2 101HEMB01/02 studies. Blood Adv. 2025 9 12 2980 2987 10.1182/bloodadvances.2024015184 40197980
    [Google Scholar]
  30. De Wolf D. Singh K. Chuah M.K. VandenDriessche T. Hemophilia gene therapy: The end of the beginning? Hum. Gene Ther. 2023 34 17-18 782 792 10.1089/hum.2023.112 37672530
    [Google Scholar]
  31. Stephens C.J. Lauron E.J. Kashentseva E. Lu Z.H. Yokoyama W.M. Curiel D.T. Long-term correction of hemophilia B using adenoviral delivery of CRISPR/Cas9. J. Control. Release 2019 298 128 141 10.1016/j.jconrel.2019.02.008
    [Google Scholar]
  32. Wahane A. Waghmode A. Kapphahn A. Dhuri K. Gupta A. Bahal R. Role of Lipid-based and polymer-based non-viral vectors in nucleic acid delivery for next-generation gene therapy. Molecules 2020 25 12 2866 10.3390/molecules25122866 32580326
    [Google Scholar]
/content/journals/cgt/10.2174/0115665232413510250904105956
Loading
Advances in Gene Therapy Clinical Trials for Hemophilia Care
Bentham Science Publishers ; https://doi.org/10.2174/0115665232413510250904105956
/content/journals/cgt/10.2174/0115665232413510250904105956
/content/journals/cgt/10.2174/0115665232413510250904105956
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: immunogenicity ; gene editing ; hemophilia ; adeno-associated virus ; Blood coagulation factors ; clinical trials

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