Immune Profiling of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration in Mice

Authors

Maria Chen
Boram Kim
Maria I Jarvis
Samantha Fleury
Shuyun Deng
Shirin Nouraein
Susan Butler
Sangsin Lee
Courtney Chambers
H Courtney Hodges
Jerzy O Szablowski
Junghae Suh
Omid Veiseh

Publication Date

5-1-2023

Journal

Gene Therapy

DOI

10.1038/s41434-022-00371-0

PMID

36372846

PMCID

PMC10183056

PubMedCentral® Posted Date

5-20-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Dependovirus, Gene Transfer Techniques, Genetic Therapy, Immunoglobulin M, Genetic Vectors, Adeno-associated viruses, Vectors, Gene delivery, Immunotherapy, Blood-brain barrier, Brain delivery, Immunogenicity

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 responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector re-administration. Additionally, we found that IgG depletion alone was insufficient to enable re-administration, suggesting IgM antibodies play an important role in the immune response against AAV. Further, we found that AAV-mediated transduction is improved in µMT mice that lack functional IgM heavy chains and cannot form mature B-cells relative to wild-type mice. Combined, our results suggest that B-cells, including non-class switched B-cells, are 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 repeated dosing for more efficient gene delivery from AAVs.