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Investigation of Cas9 antibodies in the human eye

Author

Listed:
  • Marcus A. Toral

    (Stanford University
    University of Iowa)

  • Carsten T. Charlesworth

    (Stanford University)

  • Benjamin Ng

    (Stanford University
    University of Oxford)

  • Teja Chemudupati

    (Stanford University)

  • Shota Homma

    (Stanford University)

  • Hiromitsu Nakauchi

    (Stanford University
    Stanford University School of Medicine
    University of Tokyo)

  • Alexander G. Bassuk

    (University of Iowa)

  • Matthew H. Porteus

    (Stanford University)

  • Vinit B. Mahajan

    (Stanford University
    Veterans Affairs Palo Alto Health Care System, Palo Alto, CA)

Abstract

Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR–Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR–Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than systemically.

Suggested Citation

  • Marcus A. Toral & Carsten T. Charlesworth & Benjamin Ng & Teja Chemudupati & Shota Homma & Hiromitsu Nakauchi & Alexander G. Bassuk & Matthew H. Porteus & Vinit B. Mahajan, 2022. "Investigation of Cas9 antibodies in the human eye," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28674-1
    DOI: 10.1038/s41467-022-28674-1
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    References listed on IDEAS

    as
    1. Jonathan Strecker & Sara Jones & Balwina Koopal & Jonathan Schmid-Burgk & Bernd Zetsche & Linyi Gao & Kira S. Makarova & Eugene V. Koonin & Feng Zhang, 2019. "Engineering of CRISPR-Cas12b for human genome editing," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    2. Julie M. Crudele & Jeffrey S. Chamberlain, 2018. "Cas9 immunity creates challenges for CRISPR gene editing therapies," Nature Communications, Nature, vol. 9(1), pages 1-3, December.
    3. Lucas B. Harrington & David Paez-Espino & Brett T. Staahl & Janice S. Chen & Enbo Ma & Nikos C. Kyrpides & Jennifer A. Doudna, 2017. "A thermostable Cas9 with increased lifetime in human plasma," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
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