Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice

Abstract

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune system response against these vectors is potentiated after the first administration, which prevents the clinical use of repeated administration of AAVs. Reducing immune response against AAVs while minimizing immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components towards AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector readministration. Specifically, we found that IgG depletion was insufficient to enhance readministration, suggesting the key role of B-cell mediated IgM antibodies in the immune response against AAV. Further, we also found that AAV-mediated transduction is improved compared to wild-type mice in µMT mice that lack functional IgM heavy chains and cannot form mature Bcells. Combined, our results suggest that IgM production in B cells is a potential target for therapeutics enabling AAV re-administration. Our results also suggest that the µMT mice are a potentially useful experimental model for gene delivery studies since they allow for up to 15-fold more efficient gene delivery.

Emerging optogenetics technologies in biomedical applications

“…Several approaches have been proposed to overcome this problem. One approach is to enhance the immune tolerance of the host organism, such as the use of B cell depletion and drug‐induced immune tolerance to achieve transient induction, or the incorporation of autologous cytokines, such as Treg cells, as adjuvants to modulate immune responses 71–76 . Another strategy is to optimize the rAAV capsid to evade innate immune surveillance, such as incorporating Toll‐like Receptor 9 (TLR9) inhibitory DNA sequences into the rAAV genome 77,78 .…”