Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes

Shayesteh R. Ferdosi, Radwa Ewaisha, Farzaneh Moghadam, Sri Krishna, Jin G. Park, Mo R. Ebrahimkhani, Samira Kiani () and Karen S. Anderson ()
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Shayesteh R. Ferdosi: Biodesign Institute, Arizona State University
Radwa Ewaisha: Biodesign Institute, Arizona State University
Farzaneh Moghadam: Arizona State University
Sri Krishna: Biodesign Institute, Arizona State University
Jin G. Park: Biodesign Institute, Arizona State University
Mo R. Ebrahimkhani: Arizona State University
Samira Kiani: Arizona State University
Karen S. Anderson: Biodesign Institute, Arizona State University

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09693-x

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