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Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes

Author

Listed:
  • Shayesteh R. Ferdosi

    (Biodesign Institute, Arizona State University
    Arizona State University)

  • Radwa Ewaisha

    (Biodesign Institute, Arizona State University
    Arizona State University)

  • Farzaneh Moghadam

    (Arizona State University)

  • Sri Krishna

    (Biodesign Institute, Arizona State University
    Arizona State University)

  • Jin G. Park

    (Biodesign Institute, Arizona State University)

  • Mo R. Ebrahimkhani

    (Arizona State University
    Mayo Clinic)

  • Samira Kiani

    (Arizona State University)

  • Karen S. Anderson

    (Biodesign Institute, Arizona State University
    Arizona State University)

Abstract

The CRISPR-Cas9 system has raised hopes for developing personalized gene therapies for complex diseases. Its application for genetic and epigenetic therapies in humans raises concerns over immunogenicity of the bacterially derived Cas9 protein. Here we detect antibodies to Streptococcus pyogenes Cas9 (SpCas9) in at least 5% of 143 healthy individuals. We also report pre-existing human CD8+T cell immunity in the majority of healthy individuals screened. We identify two immunodominant SpCas9 T cell epitopes for HLA-A*02:01 using an enhanced prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding and evaluated them by T cell assays using healthy donor PBMCs. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity. Our study highlights the problem of pre-existing immunity against CRISPR-associated nucleases and offers a potential solution to mitigate the T cell immune response.

Suggested Citation

  • Shayesteh R. Ferdosi & Radwa Ewaisha & Farzaneh Moghadam & Sri Krishna & Jin G. Park & Mo R. Ebrahimkhani & Samira Kiani & Karen S. Anderson, 2019. "Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09693-x
    DOI: 10.1038/s41467-019-09693-x
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    Cited by:

    1. Chady H. Hakim & Sandeep R. P. Kumar & Dennis O. Pérez-López & Nalinda B. Wasala & Dong Zhang & Yongping Yue & James Teixeira & Xiufang Pan & Keqing Zhang & Emily D. Million & Christopher E. Nelson & , 2021. "Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Siwei Li & Jingjing An & Yaqiu Li & Xiagu Zhu & Dongdong Zhao & Lixian Wang & Yonghui Sun & Yuanzhao Yang & Changhao Bi & Xueli Zhang & Meng Wang, 2022. "Automated high-throughput genome editing platform with an AI learning in situ prediction model," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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