A systematic review and meta-analysis of immunosuppressive regimens and immune-related outcomes in adeno-associated virus-based gene therapy

Significant progress has been made in adeno-associated virus (AAV)-based gene therapy. However, host immune responses remain a major challenge to its widespread clinical application, making immunosuppressive regimens an important component of clinical management. We performed a systematic review and meta-analysis to characterize immunosuppressive regimens and immune-related outcomes in clinical AAV gene therapy. The primary outcomes were the proportions of humoral immune responses, gene therapy-associated uveitis (GTAU), elevated alanine aminotransferase (ALT), and elevated creatine kinase (CK). A total of 73 studies involving 1773 participants were included and categorized as ocular (n = 31), liver (n = 22), muscle (n = 12), or central nervous system (n = 8) according to the primary target organ. Primary subgroup analyses were restricted to studies in which immunosuppression was used prophylactically. The pooled proportions of humoral immune responses were 27.7%, 75.8%, 35.2%, and 42.6% for ocular-, liver-, muscle-, and central nervous system-directed AAV gene therapy, respectively. The pooled proportions of GTAU in ocular-directed studies, elevated ALT in liver-directed studies, elevated CK in muscle-directed studies, and elevated ALT in central nervous system-directed studies were 24.2%, 49.5%, 5.1%, and 16.5%, respectively. Statistically significant regimen-based subgroup differences were observed for GTAU in ocular-directed studies and for humoral immune responses in muscle-directed studies. However, the current evidence does not establish the superiority of any specific immunosuppressive regimen. These findings highlight variation in immune-related outcomes across target organs and the need for more clinical studies with standardized outcome reporting to better inform immunosuppressive strategies in AAV gene therapy.