Complement system response to adeno-associated virus (AAV) vector gene therapy.

Adeno-associated virus (AAV) vectors represent a novel tool for the delivery of genetic therapeutics and enable the treatment of a wide range of diseases. Success of this new modality is challenged, however, by cases of immune-related toxicities that complicate the clinical management of patients and potentially limit the therapeutic efficacy of AAV gene therapy. While significant progress has been made to manage immune-related liver enzyme elevations following systemic AAV delivery in humans, recent clinical trials utilizing high vector doses have highlighted a new challenge to AAV gene transfer - activation of the complement system. While current in vitro models implicate AAV-specific antibodies in the initiation of the classical complement pathway (CP), evidence from in vivo pre-clinical and clinical studies suggests that the alternative pathway (AP) also contributes to complement activation. A convergence of AAV-specific, environmental, and patient-specific factors shaping complement responses likely contribute to differential outcomes seen in clinical trials, from priming of the adaptive immune system to serious adverse events (SAEs) such as hepatotoxicity and thrombotic microangiopathy (TMA). Research focused on the interplay of patient-specific and AAV-related factors driving complement activation is needed, to understand and identify critical components in the complement cascade to target, and devise strategies to mitigate vector-related immune responses.