Practical Implications of Factor IX Gene Transfer for Individuals with Hemophilia B: A Clinical Perspective.

Abstract

Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement. The safety profile of AAV-mediated gene therapy also appears positive, with manageable, asymptomatic increases in liver enzymes being the most commonly described adverse event. Examining a clinical case in hemophilia B more closely, gene transfer decreased annualized bleeds from six (unknown or spontaneous) bleeds before treatment to three (spontaneous) bleeds after treatment alongside a 55% reduction in FIX replacement. The participant experienced an increase in traumatic bleeds after treatment, which appears to reflect increased physical activity and early prophylaxis discontinuation. After the gene transfer, the participant considered his hemophilia to be "cured," which emphasizes the need to manage patient expectations, particularly regarding activity levels and bleed risk in the immediate post-treatment period. Gene therapy for hemophilia has the potential to transform the lives of affected individuals and is likely to create a new class of hemophilia patient who has shifted from a severe to a mild phenotype. Despite having a mild phenotype, these individuals may retain a legacy of increased bleed risk and joint damage from their years with severe hemophilia and will need different clinical management compared to a more typical individual with mild hemophilia.