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

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

  • Gene Ther. 2023 May;30(5):429-442. doi: 10.1038/s41434-022-00371-0.
Maria Chen # 1 2,  Boram Kim # 1,  Maria I Jarvis # 1,  Samantha Fleury 1,  Shuyun Deng 1,  Shirin Nouraein 1 3,  Susan Butler 1,  Sangsin Lee 1 3,  Courtney Chambers 4,  H Courtney Hodges 1 5,  Jerzy O Szablowski 1 3 6,  Junghae Suh 7 8 9,  Omid Veiseh 10
Affiliations

Affiliations

  • 1 Department of Bioengineering, Rice University, Houston, TX, USA.
  • 2 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
  • 3 Rice Neuroengineering Initiative, George R. Brown School of Engineering, Rice University, Houston, TX, USA.
  • 4 Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, USA.
  • 5 Center for Precision Environmental Health, Department of Molecular and Cellular Biology, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 6 Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX, USA.
  • 7 Department of Bioengineering, Rice University, Houston, TX, USA. jsuh@rice.edu.
  • 8 Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX, USA. jsuh@rice.edu.
  • 9 Department of BioSciences, Rice University, Houston, TX, USA. jsuh@rice.edu.
  • 10 Department of Bioengineering, Rice University, Houston, TX, USA. omid.veiseh@rice.edu.
  • # Contributed equally.
PMID: 36372846 DOI: 10.1038/s41434-022-00371-0
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.

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