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Hemophilia Gene Therapy: Key Principles

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Gene therapies for hemophilia are currently being studied to determine their safety and efficacy. No gene therapies for hemophilia have been approved for use.

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Gene therapy is the delivery of a functional gene to specific target cells within a patient’s body to either replace a missing gene or augment a gene that is not functioning properly.1 For people with hemophilia A, this process is intended to deliver the functional F8 gene, which is required for the production of the protein Factor VIII.2 For people with hemophilia B, the process involves the delivery of the functional F9 gene, which is required for the production of the protein Factor IX.2

Virus cells that have been stripped of their own genetic material are used as vectors to carry the functional genes, known as transgenes, to the target tissue3,4 – in the case of hemophilia, the liver is the target tissue.3 The carrier of the functional gene, known as a vector, is transduced into hepatocytes, where the transgene is released.2,3,5,6


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To explore the key principles of hemophilia gene therapy, click here to access the webinar The journey of the DNA in hemophilia gene therapy.


    A well-understood condition, hemophilia is a monogenic condition, a disease resulting from the genetic defect of a single gene.2,7

    In hemophilia A there is a mutation in the F8 gene, resulting in a lack of FVIII.7 In hemophilia B there is a mutation in the F9 gene, resulting in a lack of FIX.7 The F8 and F9 genes have been fully sequenced to further facilitate knowledge of these genes.7,8

    Tight regulation of factor levels is not required to see a potential therapeutic benefit of gene therapy.2 Even a small increase in circulating levels of FVIII or FIX may modify the bleeding phenotype.2 Therefore, the delivery of new copies of a single functional gene to a patient, and the initiation of expression of the missing factor to even some degree, may have the potential for sustained therapeutic effect and modification of the patient’s bleeding phenotype.2

    These characteristics of hemophilia make it particularly suitable for gene therapy.


    Gene therapy involves the delivery of new genetic material, a transgene, to target cells within a patient using a gene therapy vector - this process is known as transduction.1,2,9 Retroviruses and AAVs are two of the main virus types being investigated for this purpose.10 AAV vectors are the most commonly utilized vector type for hemophilia gene therapy to date.1,10

    AAV-based vectors are particularly suitable for transgene delivery because they lack any known pathogenicity towards humans. AAV-derived vectors for gene therapy are unable to replicate within humans as the endogenous genes involved in replication have been replaced by the expression cassette containing the transgene of interest.11,12

    In addition, it is possible to use different AAV vector serotypes, and to engineer specific AAV vectors to better target specific human cell types.3

    For more information about how gene therapy vectors are utilized and engineered for gene therapy for hemophilia, click here to access the section on Exploring the Building Blocks of Vector Capsid Design.


    Liver cells are the target of gene therapy in people with hemophilia since both FVIII are FIX are naturally produced in liver cells13—16

    • FVIII is produced by sinusoidal endothelial cells13,14
    • FIX is produced by hepatocytes13,14

    Specific AAV vector serotypes demonstrate tropism for liver cells and support transduction into those cells.1,6

    Once the AAV vector has released the transgene within the target cell, the transgene circulates to form an episome. Episomes can persist outside the host chromosomal DNA, but when the cell itself replicates, the transgene is not passed on to daughter cells.2,17 However, mature (post-mitotic) hepatocytes do not replicate and are long-lived.14

    To find out more about the role of the liver in gene therapy for hemophilia, click here to access the section on Hemophilia Gene Therapy and the Liver.



    Components of gene therapy vectors, or the transgenes that they contain, may prompt an immune response in patients.17—19 This may involve a non-specific innate immune response, which may occur during the initial hours and days after exposure to a foreign substance,20 and a highly specific adaptive immune response, involving humoral and cellular immunity, which can arise as a result of long-lasting immunological protection.21 The potential for such an immune response is important because it can limit the transduction and therapeutic effect of gene therapy.17-19

    Some people already have antibodies to AAV from previous natural exposure.6,11,22 These may be neutralizing or non-neutralizing antibodies.22 Neutralizing antibodies may prevent transduction,17,18,23,24 which could potentially limit therapy effectiveness.23 One approach to dealing with neutralizing antibodies is to deliver empty AAV vectors (i.e. capsids only) to “mop up” the antibodies and increase the chances of complete vectors reaching the target cells.11

    Following gene therapy administration using current approaches, a potent humoral immune response develops, blocking further AAV delivery with the same serotype, thus limiting AAV vector infusion to a single dose.19 Longer periods of follow-up are needed to ascertain the duration of therapeutic benefit of a single dose. If repeated administrations of gene therapy are required, it may be necessary to employ novel strategies to circumvent humoral immunity.19

    For more information about immunological considerations associated with gene therapy, click here to access the section on Gene therapy and the immune system.


1. Kumar SR, et al. Mol Ther Methods Clin Dev 2016;3:16034. 2. Lheriteau E, et al. Blood Rev 2015;29(5):321–8. 3. Choi VW, et al. Curr Gene Ther 2005;(3):299–310. 4. High KA, Roncaralo MG. N Engl J Med 2019;381:455–64. 5. Colella P, et al. Mol Ther Methods Clin Dev 2018;8:87–104. 6. Naso MF, et al. BioDrugs 2017;31:317–34. 7. Doshi BS, Arruda VR. Ther Adv Hematol 2018;9(9):273–93. 8. Peyvandi F, et al. Blood 2013;122:3423–31. 9. Bouard D, et al. Brit J Pharmacol 2009;157:153–65. 10. Thomas CE, et al. Nat Rev Genet 2003;4(5):346–58. 11. Mingozzi F, et al. Blood 2013;122(1):23–36. 12. Santiago-Ortiz JL, Schaffer DV. J Control Release 2016;240:287–301. 13. Evens H, et al. Haemophilia 2018;24:50–9. 14. VandenDriessche T, et al. Hum Gene Ther 2017;28:1013–23. 15. Arruda VR. Haematologica 2015;100:849–50. 16. Tatsumi K, et al. Cell Med 2012;3:25–31. 17. George LA. Blood Adv 2017;1(26):2591–9. 18. Baruteau J, et al. J Inherit Metab Dis 2017;40(4):497–517. 19. Kattenhorn LM, et al. Hum Gene Ther 2016;27(12):947–61. 20. Alberts B, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Chapter 25: Innate immunity. 21. Alberts B, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Chapter 24: The Adaptive Immune System. 22. Scallan CD, et al. Blood 2006;107:1810–7. 23. Bertin B, et al. Scientific Reports 2020;864. 24. Rapti K, et al. Mol Ther 2012;20:73–83.

Date of preparation: April 2021

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