Recombinant adeno-associated virus (rAAV) has attracted a significant research focus for
delivering genetic therapies to target cells. This non-enveloped virus has been trialed in
many clinical-stage therapeutic strategies but important obstacle in clinical translation is
the activation of both innate and adaptive immune response to the protein capsid, vector
genome and transgene product. In addition, the normal population has pre-existing
neutralizing antibodies against wild-type AAV, and cross-reactivity is observed between
different rAAV serotypes. While extent of response can be influenced by dosing,
administration route and target organ(s), these pose concerns over reduction or
complete loss of efficacy, options for re-administration, and other unwanted
immunological sequalae such as local tissue damage. To reduce said immunological
risks, patients are excluded if they harbor anti-AAV antibodies or have received gene
therapy previously. Studies have incorporated immunomodulating or suppressive
regimens to block cellular and humoral immune responses such as systemic
corticosteroids pre- and post-administration of Luxturna® and Zolgensma®, the two
rAAV products with licensed regulatory approval in Europe and the United States. In this
review, we will introduce the current pharmacological strategies to immunosuppress or
immunomodulate the host immune response to rAAV gene therapy