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

Michael R. Emami; Alejandro Espinoza; Courtney S. Young; Feiyang Ma; Philip K. Farahat; Philip L. Felgner; Jeffrey S. Chamberlain; Xiangmin Xu; April D. Pyle; Matteo Pellegrini; S. Armando Villalta; Melissa J. Spencer

Molecular Therapy: Methods & Clinical Development (Sep 2023)

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

Michael R. Emami,
Alejandro Espinoza,
Courtney S. Young,
Feiyang Ma,
Philip K. Farahat,
Philip L. Felgner,
Jeffrey S. Chamberlain,
Xiangmin Xu,
April D. Pyle,
Matteo Pellegrini,
S. Armando Villalta,
Melissa J. Spencer

Affiliations

Michael R. Emami: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Alejandro Espinoza: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences – The Collaboratory, University of California, Los Angeles, Los Angeles, CA, USA
Courtney S. Young: MyoGene Bio, San Diego, CA, USA
Feiyang Ma: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Philip K. Farahat: Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
Philip L. Felgner: Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
Jeffrey S. Chamberlain: Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, WA, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
Xiangmin Xu: Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA, USA
April D. Pyle: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
Matteo Pellegrini: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, USA
S. Armando Villalta: Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA; Institute of Immunology, University of California, Irvine, Irvine, CA, USA; Department of Neurology, University of California, Irvine, Irvine, CA, USA
Melissa J. Spencer: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Corresponding author: Melissa J. Spencer, Department of Neurology, David Geffen School of Medicine, University of California, 635 Charles E. Young Dr South, NRB Rm. 401, Los Angeles, CA 90095, USA.

Journal volume & issue: Vol. 30
pp. 90 – 102

Abstract

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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.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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