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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 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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Fig. 1: Re-administration of AAV in the panel of immune-deficient mice.
Fig. 2: Neutralizing, IgM, and IgG antibody profiles after single and double injection.
Fig. 3: Biodistribution of single and double AAV administrations in WT mice.
Fig. 4: Re-administration of AAV does not alter splenic immune composition.
Fig. 5: Antibody cocktail depletion of B- and T-Cells in C57BL/6 mice.
Fig. 6: Re-administration of CAG-NLS-GFP PHP.eB to the brain.

Data availability

The main data of this study are available within this published article and its supplementary information file. The raw and analyzed datasets generated during the study are available for research purposes from the corresponding author on reasonable request. scRNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database, with series accession number GSE200223.

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Acknowledgements

The authors acknowledge the use of equipment at the Shared Equipment Authority of Rice University and a Rice University Academy Fellowship to MIJ. The authors would also like to acknowledge the support of the Single Cell Genomics Core at Baylor College of Medicine, partially supported by NIH shared instrument grants (S10OD023469, S10OD025240) and P30EY002520.

Funding

This work was supported by the National Institutes of Health under grant numbers grant numbers R01CA272769 (HCH), R01CA207497 (JS), F30HL146032 (MC), F31AI161906-01A1 (CC), and the Cancer Prevention Research Institute of Texas grant number RR160047 (OV).

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Conceptualization: MC, BK, MIJ, JS, OV. Methodology: MC, BK, MIJ, SF, SD, SN, SB, SL, CC, HCH, JOS, JS, OV. Investigation: MC, BK, MIJ, SF, SD, SN, SB, SL, CC. Visualization: MC, BK, MIJ, SF, SN, SL, CC. Supervision: HCH, JOS, JS, OV. Writing: MC, BK, MIJ, SF, SN, SL, CC, HCH, JOS, JS, OV.

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Correspondence to Junghae Suh or Omid Veiseh.

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JS is an employee of Biogen Inc. as of 2019. OV is a member of the Scientific Advisory Board of Sigilon Therapeutics and holds equity in the Avenge Bio and Pana Bio. The remaining authors declare no competing interests.

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Chen, M., Kim, B., Jarvis, M.I. et al. Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice. Gene Ther (2022). https://doi.org/10.1038/s41434-022-00371-0

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