Clinical immunogenicity in rAAV gene therapy: Insights and implications

Abstract

Recombinant adeno-associated viruses (rAAV) provide prolonged therapeutic protein expression in multiple target organs after single administration, delivering significant clinical benefits with a well-characterized safety profile, and can be further supported by active immune management strategies. Systemic rAAV gene therapy is associated primarily with transient hepatocellular injury, while complement-mediated thrombotic microangiopathy and immune-related cardiac events occur in specific contexts; DRG-associated neurotoxicity remains predominantly nonclinical with only isolated suspected human cases. The extent, kinetics, and clinical consequences of immune activation are influenced by vector-related factors, dose, route of administration, and patient-specific characteristics. Hence, the immune responses may vary significantly across products, treatment regimens, and patient populations. These responses depend on disease indication, dosing and immunosuppression regimens, route of administration, vector serotypes, and underlying immune status. Significant progress has been made in understanding mechanistic and clinical aspects of rAAV immunogenicity. Strategies for clinically managing immunogenicity are being developed to achieve desired efficacy, minimize immune-mediated adverse events, and potentially expand treatment options for patients with or without previous AAV exposure. This review focuses on clinical manifestations of immune responses to rAAV, temporal patterns of these safety events and underlying immunological mechanisms, and discusses clinical considerations, risk assessment, and potential emerging immunogenicity mitigation strategies.