Update on clinical gene therapy for hemophilia

Abstract

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) have now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral vectors with different viral capsids that have been engineered to express high-level, 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 preexisting 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.

Figure 1.

Summary of immunological challenges and successes of liver-directed AAV gene therapy for hemophilia in humans. This is a representation of hepatocytes and LSEC-lined blood vessel within the liver. After intravenous delivery of an AAV vector, viral particles enter the hepatocyte, escape the endosome, and deliver their genetic payload to the nucleus. Preclinical animal models show that FVIII or FIX expression in the liver induces immunological tolerance through conversion of effector CD4⁺ T cells into Treg. Treg suppress activation of both B- and T-cell responses directed against FVIII or FIX. Preexisting NAB to the AAV capsid can block hepatocyte gene delivery and prevent therapeutic correction of the bleeding diathesis. On successful gene delivery to hepatocytes, primary or recall immune responses may lead to activation of capsid-specific cytotoxic CD8⁺ T cells and targeted elimination of hepatocytes presenting AAV capsid epitopes on MHC class I. Preclinical animal models of severe hemophilia show that suboptimal gene delivery may fail to induce tolerance to the transgene product because a threshold level of FVIII or FIX expression is needed for successful activation of Treg. In the absence of Treg, effector CD4⁺ T cells may become activated on recognition of FVIII or FIX epitopes presented on MHC class II, which is primarily expressed on professional antigen presenting cells. The resulting T help promotes B-cell maturation, leading to the production of high-affinity class-switched antibodies and terminal differentiation into antibody secreting plasma cells.