Update on clinical gene therapy for hemophilia

George Q. Perrin, Roland W. Herzog and David M. Markusic


In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a lasting cure with a single drug administration. Near to complete correction of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) has now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral (AAV) vectors with different viral capsids and engineered to express high-levels and in some cases hyperactive coagulation factors were employed. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors (or alternative drugs that promote coagulation), and may therefore ultimately also reduce treatment costs. However, mild liver toxicities have been observed in some patients receiving high vector doses. In some but not all instances, the toxicities correlated with a T cell response directed against the viral capsid, prompting use of immune suppression. In addition, not all patients can be treated because of pre-existing immunity to viral capsids. Nonetheless, studies in animal models of hemophilia suggest that the approach can also be used for immune tolerance induction, to prevent or eliminate inhibitory antibodies against coagulation factors. These can form in traditional protein replacement therapy and represent a major complication of treatment. The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development.

  • Submitted July 2, 2018.
  • Accepted September 21, 2018.