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.
Keywords
gene therapy - hemophilia - inherited bleeding disorders - AAV - lentiviral - factor
IX - factor VIII
