Gene Therapy for Inherited Bleeding Disorders

Abstract

Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.

Fig. 1

(Color online) Theoretical pharmacokinetic limitations of replacement therapies compared with gene therapy. Multiple doses (top arrows) of replacement therapies are required to maximize the time within the therapeutic window (green), resulting in a saw-tooth shaped graph of activity versus time (blue solid line). To achieve a clinically feasible administration frequency, replacement therapy may result in peak levels in the supratherapeutic range and trough levels in the subtherapeutic range, which can be associated with thrombosis and bleeding, respectively. The time outside the therapeutic window will depend on the pharmacokinetics of the replacement therapy including the recovery and half-life. Replacement therapies with short half-lives, such as FVII and FVIIa, are especially at risk for this problem. The pharmacokinetics of transgene levels after gene therapy administration (purple dashed line) largely avoid this risk by providing the continuous stable expression levels.

Fig-2

impact of adaptive immune responses to AAV on gene transfer efficacy. Both neutralizing antibodies and cytotoxic T cells limit AAV-based gene transfer. In the absence of neutralizing antibodies and a cytotoxic T cell response, AAV liver-directed gene therapy results in transgene expression (top). The cytotoxic T cell response can limit transgene expression if not treated with immunosuppression (middle). Neutralizing antibodies to the AAV capsid can prevent efficient transduction for systemically administered AAV and prevent transgene expression (bottom). AAV, adeno-associated virus.