Overview of gene therapy for hemophilia: questions and answers to navigate the innovation

Hemophilia is a rare inherited bleeding disorder affecting approximately 1.1 million individuals worldwide, characterized by deficiency in clotting factor (F)VIII (hemophilia A) or FIX (hemophilia B). Despite advances in prophylactic factor replacement therapy and nonfactor treatments, persons with hemophilia continue to experience breakthrough bleeding, joint deterioration, and treatment burden, highlighting the need for transformative therapeutic approaches. This educational review provides a comprehensive overview of gene therapy developments for hemophilia, focusing on adenoassociated virus (AAV)-based approaches, their clinical implementation, and multidisciplinary care requirements. Gene therapy represents a paradigm shift in hemophilia treatment by addressing the underlying genetic cause through a potentially 1-time intervention. AAV-based gene therapies have demonstrated sustained factor expression in clinical trials, with persons with hemophilia, achieving factor levels in the normal or mild hemophilia range and significant reductions in bleeding rates. Recent phase III trials of valoctocogene roxaparvovec (hemophilia A) and etranacogene dezaparvovec (hemophilia B) have shown durable factor expression for up to 5 years, with the FIX-Padua variant enhancing treatment efficacy 5- to 8-fold. However, approximately 20% to 90% of persons with hemophilia experience transaminase elevation postinfusion, requiring immunosuppressive management and hepatologic monitoring. Gene therapy for hemophilia has evolved from experimental concept to clinical reality, offering sustained hemostatic protection with reduced treatment burden. While challenges remain regarding long-term durability, immune responses, and standardized care pathways, current AAV-based therapies represent a transformative advance. Future developments including alternative vectors, enhanced factor variants, and gene editing technologies promise to further improve treatment outcomes and expand patient access.