Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial

Abstract

Over the past decade, vectors derived from adeno-associated virus (AAV) have established themselves as a powerful tool for in vivo gene transfer, allowing long-lasting and safe transgene expression in a variety of human tissues. Nevertheless, clinical trials demonstrated how B and T cell immune responses directed against the AAV capsid, likely arising after natural infection with wild-type AAV, might potentially impact gene transfer safety and efficacy in patients. Seroprevalence studies have evidenced that most individuals carry anti-AAV neutralizing antibodies that can inhibit recombinant AAV transduction of target cells following in vivo administration of vector particles. Likewise, liver- and muscle-directed clinical trials have shown that capsid-reactive memory CD8 + T cells could be reactivated and expanded upon presentation of capsid-derived antigens on transduced cells, potentially leading to loss of transgene expression and immune-mediated toxicities. In celebration of the 25th anniversary of the European Society of Gene and Cell Therapy, this review article summarizes progress made during the past decade in understanding and modulating AAV vector immunogenicity. While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer.

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Cited by papers we hold 6

• Viral Vector-Based Gene Therapy · 2023
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• Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper · 2022
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• rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis · 2022
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• Gene Therapy Advances: A Meta-Analysis of AAV Usage in Clinical Settings · 2022
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• Answered and Unanswered Questions in Early-Stage Viral Vector Transduction Biology and Innate Primary Cell Toxicity for Ex-Vivo Gene Editing · 2021
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• Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions · 2021
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