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Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy.

Authors
  • Emami, Michael R1
  • Espinoza, Alejandro2, 3, 4
  • Young, Courtney S5
  • Ma, Feiyang6
  • Farahat, Philip K7
  • Felgner, Philip L7
  • Chamberlain, Jeffrey S8, 9, 10, 11
  • Xu, Xiangmin12
  • Pyle, April D13, 14
  • Pellegrini, Matteo3, 15
  • Villalta, S Armando7, 16, 17
  • Spencer, Melissa J1, 14
  • 1 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 3 Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 4 Institute for Quantitative and Computational Biosciences - The Collaboratory, University of California, Los Angeles, Los Angeles, CA, USA.
  • 5 MyoGene Bio, San Diego, CA, USA.
  • 6 Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 7 Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • 8 Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
  • 9 Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, WA, USA.
  • 10 Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA.
  • 11 Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
  • 12 Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA, USA.
  • 13 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 14 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
  • 15 Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 16 Institute of Immunology, University of California, Irvine, Irvine, CA, USA.
  • 17 Department of Neurology, University of California, Irvine, Irvine, CA, USA.
Type
Published Article
Journal
Molecular Therapy — Methods & Clinical Development
Publisher
Elsevier
Publication Date
Sep 14, 2023
Volume
30
Pages
90–102
Identifiers
DOI: 10.1016/j.omtm.2023.06.002
PMID: 37746243
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced immune responses. Here, we show that mice dual-dosed with AAV9 at 4-week intervals better recapitulate aspects of human immunity to AAV. In the model, anti-AAV9 immunoglobulin G (IgGs) increased in a linear fashion between the first and second AAV administrations. Complement activation was only observed in the presence of high levels of both AAV and anti-AAV IgG. Myeloid-derived pro-inflammatory cytokines were significantly induced in the same pattern as complement activation, suggesting that myeloid cell activation to AAV may rely on the presence of both AAV and anti-AAV IgG complexes. Single-cell RNA sequencing of peripheral blood mononuclear cells confirmed that activated monocytes were a primary source of pro-inflammatory cytokines and chemokines, which were significantly increased after a second AAV9 exposure. The same activated monocyte clusters expressed both Fcγ and complement receptors, suggesting that anti-AAV-mediated activation of myeloid cells through Fcγ receptors and/or complement receptors is one mechanism by which anti-AAV antigen complexes may prime antigen-presenting cells and amplify downstream immunity. © 2023 The Authors.

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