Liver dysfunction in AAV-mediated Hemophilia B gene therapy: Mechanisms and management strategies

Hemophilia B, an X-linked recessive bleeding disorder caused by mutations in the gene encoding coagulation factor IX (FIX). Gene therapy using adeno-associated viral (AAV) vectors targeting hepatocytes has emerged as a promising treatment, enabling sustained FIX expression. However, AAV vectors exhibit strong liver tropism, often triggering immune responses that lead to hepatotoxicity. Clinical trials involving Etranacogene Dezaparvovec, Fidanacogene Elaparvovec, and BBM-H901 (Dalnacogene Ponparvovec) reported transient elevations in liver enzymes, typically occurring 2-6 weeks post-infusion. These elevations are usually mild to moderate and respond well to corticosteroid-based immunosuppression. The hepatic complications, while manageable, pose a risk to therapeutic efficacy and highlight the need for careful monitoring, early detection, and personalized immunosuppressive strategies. This review explores the mechanisms of AAV-induced liver dysfunction in gene therapy for Hemophilia B, with a focus on clinical manifestations, immune-mediated pathogenesis, and emerging approaches for mitigating liver-related adverse effects and providing clinical guidance.