ArticleNature communications2022
A kinetic model predicts SpCas9 activity, improves off-target classification, and reveals the physical basis of targeting fidelity.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Pooled it
- Article
- CrisprPr: a hybrid-driven framework for CRISPR/Cas9 off-target prediction with analysis of prior-information updates.Briefings in bioinformatics · 2026Article
- Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges.Molecular therapy. Nucleic acids · 2025Review
- The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus.Nature communications · 2025Article
- Controlling DNA-RNA strand displacement kinetics with base distribution.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Learning to utilize internal protein 3D nanoenvironment descriptors in predicting CRISPR-Cas9 off-target activity.NAR genomics and bioinformatics · 2025Article
- A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent.Nucleic acids research · 2025Article
- Dynamic basis of supercoiling-dependent DNA interrogation by Cas12a via R-loop intermediates.Nature communications · 2025Article
- Modulation of CRISPR-Cas9 Cleavage with an Oligo-Ribonucleoprotein Design.Chembiochem : a European journal of chemical biology · 2025Article
- Structural basis of Cas9 DNA interrogation with a 5' truncated sgRNA.Nucleic acids research · 2025Article
- Iterative crRNA design and a PAM-free strategy enabled an ultra-specific RPA-CRISPR/Cas12a detection platform.Communications biology · 2024Article
- Logical regulation of endogenous gene expression using programmable, multi-input processing CRISPR guide RNAs.Nucleic acids research · 2024Article
- AlPaCas: allele-specific CRISPR gene editing through a protospacer-adjacent-motif (PAM) approach.Nucleic acids research · 2024Article
- Genome-wide CRISPR off-target prediction and optimization using RNA-DNA interaction fingerprints.Nature communications · 2023Article
- Guide-specific loss of efficiency and off-target reduction with Cas9 variants.Nucleic acids research · 2023Article
- Article
- Titrating CD47 by mismatch CRISPR-interference reveals incomplete repression can eliminate IgG-opsonized tumors but limits induction of antitumor IgG.PNAS nexus · 2023Article
- The energy landscape for R-loop formation by the CRISPR-Cas Cascade complex.Nature structural & molecular biology · 2023Article
- High-throughput biochemistry in RNA sequence space: predicting structure and function.Nature reviews. Genetics · 2023Review
Corrections and comments
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Authors and funding
8 authors at 6 institutions in 4 countries.
Funding
Abstract
The S. pyogenes (Sp) Cas9 endonuclease is an important gene-editing tool. SpCas9 is directed to target sites based on complementarity to a complexed single-guide RNA (sgRNA). However, SpCas9-sgRNA also binds and cleaves genomic off-targets with only partial complementarity. To date, we lack the ability to predict cleavage and binding activity quantitatively, and rely on binary classification schemes to identify strong off-targets. We report a quantitative kinetic model that captures the SpCas9-mediated strand-replacement reaction in free-energy terms. The model predicts binding and cleavage activity as a function of time, target, and experimental conditions. Trained and validated on high-throughput bulk-biochemical data, our model predicts the intermediate R-loop state recently observed in single-molecule experiments, as well as the associated conversion rates. Finally, we show that our quantitative activity predictor can be reduced to a binary off-target classifier that outperforms the established state-of-the-art. Our approach is extensible, and can characterize any CRISPR-Cas nuclease - benchmarking natural and future high-fidelity variants against SpCas9; elucidating determinants of CRISPR fidelity; and revealing pathways to increased specificity and efficiency in engineered systems.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.