Multifunctional CRISPR-Cas9 with Engineered Immunosilenced Human T Cell Epitopes
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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.
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Cas9 proteins can be modified to eliminate immunodominant epitopes through targeted mutations while preserving function and specificity.
“This finding demonstrated that Cas9 proteins can be modified to eliminate immunodominant epitopes through targeted mutations while preserving its function and specificity (Figure 2) [96].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [96]
SpCas9 with mutations in selected immunodominant epitopes delivered to healthy donor B-cell APCs resulted in significantly decreased T-cell response.
“When SpCas9 with mutations in the selected epitopes was delivered to healthy donor B-cell APCs, the measured T-cell response had significantly decreased.”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [96]
High prevalence of preexisting cellular immunity against Cas9 (Cas9-reactive T-cells) has been identified.
“Furthermore, a high prevalence of preexisting cellular immunity against Cas9 (Cas9-reactive T-cells) has also been identified2–4.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [2]
Some studies have found preexisting serum α-Cas9 to be present in only 2.5-10% of large human cohorts.
“some studies have found preexisting serum α-Cas9 to be present in only 2.5–10% of large human cohorts1,2.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [2]
Multiple groups have reported high frequencies (>60% of patients) of Cas9 reactive T-cells in humans.
“multiple groups have reported high frequencies (>60% of patients) of Cas9 reactive T-cells in humans2–4.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [2]
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- Authors
- Ferdosi, S. R., Ewaisha, R., Moghadam, F., Krishna, S., Park, J. G., Ebrahimkhani, M. R., Kiani, S., & Anderson, K. S.
- Affiliations
- Arizona State University (US)
- Mayo Clinic (US)
- Corresponding author
- Kiani, Samira
- Anderson, Karen S.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-04-23
- Volume
- 10
- Issue
- 1
- Pages
- 1842-1842
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6478683
- OpenAlex
- W2950183003
- Cited by
- 204
- References
- 60
- Citations by year
- 2026: 17 · 2025: 36 · 2024: 23 · 2023: 31 · 2022: 31 · 2021: 26 · 2020: 27 · 2019: 12 · 2018: 1
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Massachusetts General Hospital
- Defense Advanced Research Projects Agency (D16AP00047)
- National Institute of Biomedical Imaging and Bioengineering (R01EB024562)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- CRISPR/Cas9, SpCas9, T cell epitopes, CD8+ T cell immunity, HLA-A*0201, epitope prediction, immunogenicity, gene therapy, personalized gene therapy
- MeSH terms
- CRISPR-Associated Protein 9, Antibodies, Bacterial, Antigen-Presenting Cells, Humans, Lymphocyte Activation, Streptococcus pyogenes, HLA-A Antigens, Genetic Therapy, Mutagenesis, CD8-Positive T-Lymphocytes, Epitope Mapping, Epitopes, T-Lymphocyte, Precision Medicine, HEK293 Cells, Cell Engineering, Healthy Volunteers
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