Transient prophylactic immunosuppression with abatacept or dasatinib prevents immune responses in AAV gene transfer.

Immune responses against the adeno-associated virus (AAV) vector capsid and transgene product pose significant hurdles to the efficacy and safety of gene therapy. Antibodies to the capsid can cause complement activation and prevent redosing, while T cell responses can mediate liver toxicity. Furthermore, responses against the transgene product can negatively impact therapy and cause tissue toxicities. Here, we investigated transient prophylactic immunosuppression at the time of AAV dosing as a means of mitigating immune responses, employing two clinically approved but mechanistically distinct drugs: abatacept, a CTLA-4-Ig fusion blocking T cell costimulation, and dasatinib, a small-molecule SRC kinase inhibitor that targets T cell receptor signaling. Results in mouse models demonstrate that both drugs can fully block neutralizing antibody formation against capsid, enable redosing by the systemic route, and suppress CD8+ T cell responses against capsid, albeit abatacept showed overall greater efficacy. Furthermore, both drugs inhibited adaptive responses against transgene products such as human Factor IX and ovalbumin. These findings identify two clinically viable strategies for managing both humoral and cellular immunity to AAV and its cargo. Due to its selectivity, pharmacokinetics/pharmacodynamics, and safety properties, abatacept appears particularly promising as an immunosuppressant that could critically improve the clinical translatability of AAV gene therapy.