Identification of preexisting adaptive immunity to Cas9 proteins in humans
Open accessPublished version of a preprint
Abstract
The CRISPR-Cas9 system is a powerful tool for genome editing, which allows the precise modification of specific DNA sequences. Many efforts are underway to use the CRISPR-Cas9 system to therapeutically correct human genetic diseases 1-6. The most widely used orthologs of Cas9 are derived from Staphylococcus aureus and Streptococcus pyogenes 5,7. Given that these two bacterial species infect the human population at high frequencies 8,9, we hypothesized that humans may harbor preexisting adaptive immune responses to the Cas9 orthologs derived from these bacterial species, SaCas9 (S. aureus) and SpCas9 (S. pyogenes). By probing human serum for the presence of anti-Cas9 antibodies using an enzyme-linked immunosorbent assay, we detected antibodies against both SaCas9 and SpCas9 in 78% and 58% of donors, respectively. We also found anti-SaCas9 T cells in 78% and anti-SpCas9 T cells in 67% of donors, which demonstrates a high prevalence of antigen-specific T cells against both orthologs. We confirmed that these T cells were Cas9-specific by demonstrating a Cas9-specific cytokine response following isolation, expansion, and antigen restimulation. Together, these data demonstrate that there are preexisting humoral and cell-mediated adaptive immune responses to Cas9 in humans, a finding that should be taken into account as the CRISPR-Cas9 system moves toward clinical trials.
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Long-term expression of genome editing molecules may expose patients to undesired off-target editing or immune reactions.
“Second, long-term expression of genome editing molecules may expose patients to undesired off-target editing or immune reactions 66,67 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [66]
The Abstract says prolonged Cas9 expression in in vivo therapies may provoke a cytotoxic T-cell response and possible organ toxicity. It does not link long-term expression to increased off-target editing; it describes CRISPR-Cas9 as having limited off-target effects. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPre-existing Cas9 antibodies and reactive T-cells have been detected in humans exposed to pathogenic bacteria harboring CRISPR systems.
“Pre-existing Cas9 antibodies and reactive T-cells have been detected in humans exposed to pathogenic bacteria harboring CRISPR systems, although it is unknown whether these are present at concentrations sufficient to trigger an immune response to the genome editing enzymes 66,104 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [66]
The paper’s Abstract reports anti-Cas9 antibodies and Cas9-reactive T cells in human donors, and notes that S. aureus and S. pyogenes are common bacteria that can be pathogenic. It does not establish that the tested donors had been exposed to those bacteria. It also says the clinical impact requires further study, but does not specifically assess whether antibody or T-cell concentrations are sufficient to trigger a response to genome-editing enzymes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIt is unknown whether pre-existing Cas9 antibodies and reactive T-cells are present at concentrations sufficient to trigger an immune response to genome editing enzymes.
“although it is unknown whether these are present at concentrations sufficient to trigger an immune response to the genome editing enzymes 66,104 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [66]
The discussion passage in our copy (labeled Abstract; page unavailable) says further work is needed to determine the clinical impact of preexisting Cas9 immunity, including whether T cells kill cells presenting Cas9. That supports uncertainty about an immune response during genome editing. The paper does not frame that uncertainty as whether antibodies and T cells are present at sufficient concentrations; it reports Cas9-specific T-cell responses in laboratory assays. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOther factors affecting clinical applications of genome editing include immunogenicity of bacterially-derived editing proteins, potential for pre-existing antibodies against CRISPR components to cause inflammation, and unknown long-term safety and stability of genome editing outcomes.
“Other factors affecting clinical applications of genome editing include the immunogenicity of bacterially-derived editing proteins, the potential for pre-existing antibodies against CRISPR components to cause inflammation and the unknown long-term safety and stability of genome editing outcomes.”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [66]
The paper’s Abstract (page unavailable) reports pre-existing antibodies and T cells against bacterial Cas9 proteins and warns that immune responses may hinder clinical use. It discusses inflammation in connection with a prior gene-therapy vector, but does not establish that antibodies against CRISPR components cause inflammation. It also does not address the long-term safety or stability of genome-editing outcomes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCRISPR/Cas9-based systems for retinal gene editing have the potential for a heightened adaptive immune response given the bacterial origin of the Cas9 enzyme and high prevalence of pre-existing immunity.
“Another consideration for CRISPR/Cas9-based systems for retinal gene editing is the potential for a heightened adaptive immune response given the bacterial origin of the Cas9 enzyme and high prevalence of pre-existing immunity (Charlesworth et al., 2019).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Charlesworth et al., 2019
A study of 125 healthy adult human blood donors in the USA reported pre-existing anti-SaCas9 antibodies in 78% and anti-SpCas9 antibodies in 58% of samples.
“A study involving 125 healthy adult human blood donors in the USA with a median age of 43 reported pre-existing anti-SaCas9 antibodies and anti-SpCas9 antibodies in 78% and 58% of the total samples, respectively.”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [24]
Among tested donors, 78% had SaCas9-specific T-cells and 67% were positive for SpCas9-specific T-cells.
“Among the tested donors, 78% had SaCas9-specific T-cells and 67% were positive for SpCas9-specific T-cells.”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [24]
A majority of the general population may exhibit preexisting α-Cas9.
“While there are discrepancies regarding the exact prevalence of these antibodies in humans, a majority of the general population may exhibit preexisting α-Cas93.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [3]
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 [3]
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 [3]
The older age of our cohort may explain the lower raw ELISA A450 values we observed compared with previous work.
“This may explain the lower raw ELISA A450 values we observed compared with previous work (Table 1)3.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [3]
CRISPR-Cas9 allows genetic target-specific cleavage and editing.
“CRISPR-Cas9 is a promising therapeutic tool that allows genetic target-specific cleavage and editing (111).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [111]
The prevalence of anti-SaCas9 antibodies and T-cell in humans is reported to be 78%.
“One concern is that the prevalence of anti-SaCas9 antibodies and T-cell in humans are reported to be 78% (111).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [111]
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- Authors
- Charlesworth, C. T., Deshpande, P. S., Dever, D. P., Camarena, J., Lemgart, V. T., Cromer, M. K., Vakulskas, C. A., Collingwood, M. A., Zhang, L., Bode, N. M., Behlke, M. A., Dejene, B., Cieniewicz, B., Romano, R., Lesch, B. J., Gomez-Ospina, N., Mantri, S., Pavel-Dinu, M., Weinberg, K. I., & Porteus, M. H.
- Affiliations
- Stanford Medicine (US)
- Integrated DNA Technologies (United States) (US)
- Corresponding author
- Weinberg, Kenneth I.
- Porteus, Matthew H.
- ORCID
- Charlesworth, Carsten T.
- Dever, Daniel P.
- Camarena, Joab
- Lemgart, Viktor T.
- Cromer, M. Kyle
- Vakulskas, Christopher A.
- Collingwood, Michael A.
- Zhang, Liyang
- Bode, Nicole M.
- Behlke, Mark A.
- Dejene, Beruh
- Cieniewicz, Brandon
- Romano, Rosa
- Lesch, Benjamin J.
- Gomez-Ospina, Natalia
- Mantri, Sruthi
- Pavel-Dinu, Mara
- Weinberg, Kenneth I.
- Porteus, Matthew H.
- Venue
- Nature Medicine
- Published
- 2019-01-28
- Volume
- 25
- Issue
- 2
- Pages
- 249-254
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7199589
- OpenAlex
- W2949380898
- Cited by
- 1,093
- References
- 48
- Citations by year
- 2026: 130 · 2025: 128 · 2024: 132 · 2023: 111 · 2022: 125 · 2021: 166 · 2020: 131 · 2019: 110 · 2018: 57
- FWCI
- 44.16
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nd)
- Funders
- Amon G. Carter Foundation
- National Institutes of Health (5r01ai120766-02)
- National Institute of General Medical Sciences (T32GM119995)
- National Institute of Allergy and Infectious Diseases (R01-AI120766)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- CRISPR/Cas9, SaCas9, SpCas9, Staphylococcus aureus, Streptococcus pyogenes, humoral immune response, cell-mediated immunity, genome editing safety
- MeSH terms
- CRISPR-Associated Protein 9, Adult, Cell Separation, Female, Humans, Male, T-Lymphocytes, Adaptive Immunity, Immunity, Humoral
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