Abstract
Hemophilia A (HA) is an X-linked bleeding disorder due to deficiencies in coagulation factor VIII (FVIII). The major complication of current protein-based therapies is the development of neutralizing anti-FVIII antibodies, termed inhibitors, that block the hemostatic effect of therapeutic FVIII. Inhibitors develop in about 20–30% of people with severe HA, but the risk is dependent on the interaction between environmental and genetic factors, including the underlying F8 gene mutation. Recently, multiple clinical trials evaluating adeno-associated viral (AAV) vector liver-directed gene therapy for HA have reported promising results of therapeutically relevant to curative FVIII levels. The inclusion criteria for most trials prevented enrollment of subjects with a history of inhibitors. However, preclinical data from small and large animal models of HA with inhibitors suggests that liver-directed gene therapy can in fact eradicate pre-existing anti-FVIII antibodies, induce immune tolerance, and provide long-term therapeutic FVIII expression to prevent bleeding. Herein, we review the accumulating evidence that continuous uninterrupted expression of FVIII and other transgenes after liver-directed AAV gene therapy can bias the immune system toward immune tolerance induction, discuss the current understanding of the immunological mechanisms of this process, and outline questions that will need to be addressed to translate this strategy to clinical trials.
Highlights
Hemophilia A (HA) is an X-linked bleeding disorder due to inherited deficiency in coagulation factor VIII (FVIII) activity [1, 2]
We have previously reported on the successful immune tolerance induction in 4 inhibitor-prone HA dogs with pre-existing anticFVIII antibodies after associated viral (AAV) liver-directed gene therapy (Table 2) [100]
CFVIII inhibitors have been eradicated in 6 HA dogs (2 dogs naïve discussed in section “Immune Tolerance Induction in Naïve Hemophilia A Animal Models” and 4 dogs with pre-existing inhibitors discussed in section “Inhibitor Eradication and Immune Tolerance Induction in Hemophilia A Inhibitor Models With Pre-existing Anti-FVIII Immune Response”) by cFVIII AAV liver-directed gene therapy, which provided stringent immune tolerance and long-term therapeutically relevant cFVIII levels
Summary
Hemophilia A (HA) is an X-linked bleeding disorder due to inherited deficiency in coagulation factor VIII (FVIII) activity [1, 2]. Treatment in the developed world involved the intravenous administration of FVIII concentrates to treat or prevent bleeding. A FVIII-mimetic that is delivered subcutaneously, emicizumab, has been approved as prophylactic treatment for HA to prevent bleeding [3,4,5,6]. Emicizumab is the first approved non-factor therapy for HA, but several others are in clinical development [7, 8]. Other novel treatments for HA in clinical studies include several gene therapy approaches [9,10,11]
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