A Review of the Challenge of Pre-Existing Humoral Immunity in Adeno-Associated Virus Gene Therapy and Potential Solutions

Adeno-associated virus (AAV) vectors are promising platforms used in a growing number of approved gene therapy (GT) products across diverse therapeutic areas. Due to the potential safety and efficacy concerns associated with AAV-based immune responses, patients with pre-existing anti-AAV antibodies (Abs) are routinely excluded from GT trials to prevent treatment of patients who are hypothesized to have potentially higher risk and/or little or no benefit. However, the exclusion of seropositive patients without prior GT exposure is not based on data-driven Ab titer cut-offs, and diagnostics to identify levels of pre-existing immunity have not been standardized, precluding data generation that would substantiate or reject this hypothesis. There are also significant gaps in clinical data comparing the impact of pre-existing immunity with treatment-induced immune responses for a variety of disease states. This review aims to address these gaps by examining the impact of pre-existing anti-AAV Abs on the safety and efficacy of approved and failed GT products and ongoing clinical trials. Together, these data suggest that pre-existing immunity may not be the principal determinant of GT success. Therefore, to expand the number of patients eligible for treatment, novel AAV GTs should be optimized to mitigate against the effects of anti-AAV Abs and avoid the need for exclusionary screening; in turn, including both seronegative and seropositive patients in clinical trials will enable characterization of the clinical relevance of anti-AAV Abs. Strategies to prevent an undesirable immune response to GT, including immunosuppressive regimens and modifications to GT manufacturing, design and delivery, are presented for consideration in future GT trials.