Multiple ongoing trials are further investigating the use of gene therapy in both hemophilia A and hemophilia B, as numerous questions remain, including the long-term risks of this approach, how long the effects will persist, and whether the various rAAV vector manufacturing processes affect their efficacy and safety. Nonetheless, gene therapy clinical trials have shown long-lasting benefits. “Despite the open questions and challenges to be addressed, knowledge has progressed rapidly in the gene therapy arena, and curing hemophilia has never been this close, a pleasing prospect for both patients and health care professionals,” Drs Yamaguti-Hayakawa and Ozelo wrote.6

To learn more about advances in and challenges pertaining to gene therapy for hemophilia, Hematology Advisor sat down with Roland W Herzog, PhD, director of the Gene and Cell Therapy Program at the Herman B Wells Center for Pediatric Research at Indiana University School of Medicine in Indianapolis and editor-in-chief of Molecular Therapy Methods & Clinical Development.

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Hematology Advisor: What is the current state and potential role of gene therapy in hemophilia?

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Dr Herzog: Multiple competing clinical trials are ongoing that are based on the same principle: A gene transfer vehicle, or “vector,” in the form of the AAV vector is given intravenously to ultimately infect hepatocytes in the liver and express factor VIII or IX, which are secreted into the blood. The vectors used in the various trials  differ slightly in their design, especially in the choice of the viral capsid — the protein shell of the viral particle that contains the DNA with the therapeutic gene.

There are also differences in manufacturing methods and doses given to the patients in these trials. Three such gene therapy products are now [being studied in] phase 3 [trials], 1 for hemophilia A and 2 for hemophilia B. These advances are the results of 2 decades of basic and clinical research in gene therapy for hemophilia, which identified gene transfer to the liver with AAV vectors as the most promising approach, at least for now. 

Of the diverse methods of treating hemophilia that now exist, only gene therapy can cure the disease and provide clotting activity for more than a decade, and perhaps even much longer, without a need for frequent drug injections as is the case in protein-based therapies. Should one be able to produce gene therapy medicines at reduced costs, these may also be of interest to developing countries, whose health care systems cannot afford a continuous supply of protein drugs for lifelong repeated injections.

Hematology Advisor: What are the most notable research findings in this area thus far?

Dr Herzog: High levels of factor IX activity (near the normal range) have already been reported [as being] stable in patients for at least 3 years. This success is facilitated by use of a naturally found variant of factor IX that has much higher clotting activity so that comparatively low doses of the gene therapy vector are effective.

Curative levels of factor VIII have also been reported in multiple hemophilia A patients. As with the success in hemophilia B, patients typically did not experience bleeds and no longer required infusions of their traditional clotting factor products. However, factor VIII levels have somewhat declined, and we simply have to wait a bit to see how the gene therapy holds up in hemophilia A patients over time.  

Hematology Advisor: What are examples of the unique challenges regarding this area of investigation?

Dr Herzog: For hemophilia A, very high doses of the vector are needed. Some mild liver toxicity has been observed at the highest doses, the cause of which is not entirely clear. Duration and variability of gene therapy in hemophilia A patients have been brought into question. Longer-term follow-up of patients enrolled in multiple trials will address these questions, and vector systems and gene transfer protocols will become more refined as physicians and scientists are learning more from their patients.

A special challenge for gene therapy is almost always the immune system. Because of natural infection, most of us carry antibodies that can neutralize one or the other AAV capsid. Therefore, not all patients can receive a specific gene therapy product — because someone with a high level of preexisting antibodies to a specific capsid would not benefit from the vector injection. Even after successful gene transfer, the immune system may aim to eliminate the virus, which it perceives as a form of viral infection. In this case, transient immune suppression is applied.


  1. World Federation of Hemophilia. Report on the Annual Global Survey 2017. . Published October 2018. Accessed on December 6, 2019.
  2. Centers for Disease Control and Prevention. Data & Statistics on Hemophilia. Updated on June 21, 2019. Accessed on December 6, 2019.
  3. O’Hara J, Hughes D, Camp C, Burke T, Carroll L, Diego D-AG. The cost of severe haemophilia in Europe: the CHESS study. Orphanet J Rare Dis. 2017;12:106.
  4. Batty P, Lillicrap D. Advances and challenges for hemophilia gene therapy. Hum Mol Genet. 2019;28:R95-R101.
  5. Butterfield JSS, Hege KM, Herzog RW, Kaczmarek R. A molecular revolution in the treatment of hemophilia [published online November 12, 2019]. Mol Ther. doi:10.1016/j.ymthe.2019.11.006
  6. Yamaguti-Hayakawa GG, Ozelo MC. Gene therapy: paving new roads in the treatment of hemophilia. Semin Thromb Hemost. 2019;45:743-750.