Search-and-replace genome editing without double-strand breaks or donor DNA
Open accessAbstract
Most genetic variants that contribute to disease 1 are challenging to correct efficiently and without excess byproducts 2-5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.
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The first base directly downstream of the scaffold in the pegRNA may never be a C because it can interfere with the 3D structure of the sgRNA backbone and decrease editing efficiencies.
“the first base directly downstream of the scaffold in the pegRNA may never be a C as this can interfere with the 3D structure of the sgRNA backbone and decrease editing efficiencies.14”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [14]
In Results > Optimization of pegRNAs, the paper reports that a C immediately after the sgRNA scaffold generally lowered editing efficiency and speculates that it can disrupt guide RNA structure. It recommends avoiding C at that position, but does not say it can never be used. (LLM, conf=0.87)
Experimental — accuracy not yet measuredContrary to base editing, efficient use of prime editing uses two sgRNAs that require significant optimization, resulting in need to test multiple sgRNA combinations.
“Contrary to base editing, efficient use of prime editing uses two sgRNAs that require significant optimization for efficient use. This results in the need to test multiple sgRNA combinations to find the most effective combination65,66.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [65]
The Results sections ‘Optimization of pegRNAs’ and ‘Prime editor 3 systems (PE3, PE3b)’ describe testing pegRNA designs and alternative nicking locations to improve editing outcomes (page numbers unavailable). But the paper describes PE3 as using a pegRNA plus a separate sgRNA, not two conventional sgRNAs, and PE2 does not require the second guide. It supports optimizing guide choices, but not the claim that efficient prime editing generally requires testing multiple sgRNA combinations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAlternatives to DNA cleavage-induced editing include base editing, prime editing, and CRISPRi/CRISPRa.
“Alternatives to DNA cleavage-induced editing include using CRISPR-Cas9 for direct chemical sequence alteration (base editing) 25,26 , providing RNA templates for gene alteration (prime editing) 27,28 , and for transcriptional control (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa) 29,30 (Fig. 3).”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [28]
Experimental — accuracy not yet measuredPrime editors combine nickase-Cas9 with a reverse transcriptase and enable introduction of all point mutations and small insertions and deletions without double-stranded breaks.
“Prime editors, combining nickase-Cas9 (nCas9) with a reverse transcriptase, further expand DSBs-free genome engineering, allowing for the introduction of all point mutations and small insertions and deletions.14”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [14]
Prime editors have significantly increased the target scope of DSB-free genome engineering and can be used when no suitable base editing sgRNA can be designed or when the target mutation is an indel, small insertion or deletion.
“Prime editors have significantly increased the target scope of DSBs-free genome engineering and can be used in cases where no suitable base editing sgRNA can be designed or if the target mutation is an indel, small insertion or deletion.”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [14]
Prime editors consist of a nickase Cas9 (Cas9(H840A)) fused to a reverse transcriptase.
“Prime editors consist of a nickase Cas9 (Cas9(H840A)) fused to a reverse transcriptase.”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [14]
The reverse transcriptase in prime editors uses the RT template of the pegRNA's 3′ extension to write the edit of interest into the target site.
“The RT then directly writes your edit of interest by using the RT template of the 3′ extension.”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [14]
Even more flexibility for genome engineering without DSBs can be achieved by using prime editing.
“Even more flexibility for genome engineering without DSB’s can be achieved by using prime editing65.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [65]
Each pegRNA directs editing to the target locus and provides the reverse-transcription template needed to install the programmed variant at the endogenous site.
“Each pegRNA directs editing to the target locus and provides the reverse-transcription template needed to install the programmed variant at the endogenous site (56, 57) (Fig. 2B).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [56]
Prime editing allows for all types of desired base substitutions, small insertions up to 44 bp and deletions up to 88 bp at selected target sites with the use of CRISPR/Cas9 nickase-reverse transcriptase fusions.
“Prime editing allows for all types of desired base substitutions, small insertions up to 44 bp and deletions up to 88 bp at selected target sites with the use of CRSIPR/Cas9 nickase-reverse transcriptase fusions (Anzalone et al., 2019;Lin et al., 2020).”
From Genetic resources and precise gene editing for targeted improvement of barley abiotic stress tolerance (2023) · cites this paper as Anzalone et al., 2019
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“Researchers have developed several prime editing strategies: in PE1, wild type M-MLV RT fused to the C terminus of Cas9 (H840A) nickase; in PE2, Cas9 (H840A) with pentamutant M-MLV RT (D200N/ L603W/ T330P/ T306K/ W313F); in PE3, a PE2 prime editor with additional simple gRNA to simultaneously nick the non-edited stran…”
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First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy
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Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies
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“Even more fl exibility for genome engineering without DSB ’ s can be achieved by using prime editing 65 .”
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Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models
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A CRISPR way for accelerating cereal crop improvement: Progress and challenges
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Massively targeted evaluation of therapeutic CRISPR off-targets in cells
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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
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Genome-editing strategies for treating human retinal degenerations
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Genetic interaction mapping informs integrative structure determination of protein complexes
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PE6c greatly enhances prime editing in transgenic rice plants
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Directed evolution of hyperactive integrases for site specific insertion of transgenes
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Design of efficacious somatic cell genome editing strategies for recessive and polygenic diseases
Carlson-Stevermer, J., Das, A., Abdeen, A. A., Fiflis, D., Grindel, B. I., Saxena, S., Akcan, T., Alam, T., Kletzien, H., Kohlenberg, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20065-8 · Cited by 32 · see citing works
Recent advances in prime editing technologies and their promises for therapeutic applications
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Development of multiplexed orthogonal base editor (MOBE) systems
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Improved prime editing allows for routine predictable gene editing in <i>Physcomitrium patens</i>
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Development and application of prime editing in plants
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A microglia clonal inflammatory disorder in Alzheimer’s disease
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“Prime editing allows for all types of desired base sub‐ stitutions, small insertions up to 44 bp and deletions up to 88 bp at selected target sites with the use of CRSIPR/Cas9 nickase-reverse transcriptase fusions (Anzalone et al., 2019; Lin et al., 2020).”
CRISPR/cas-mediated genome editing in sorghum — recent progress, challenges and prospects
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Engineering rice Nramp5 modifies cadmium and manganese uptake selectivity using yeast assay system
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Rodent Genetic Models of Ah Receptor Signaling
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“…with the advent of techniques like base editing and prime editing that induce editing without double stranded breaks, further improves the range of mutations and the ease with which these specific mutations may be installed(Komor et al. 2016; Gaudelli et al. 2017; Anzalone et al. 2019).”
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Prime-editing methods and pegRNA design programs
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- Authors
- Anzalone, A. V., Randolph, P. B., Davis, J. R., Sousa, A. A., Koblan, L. W., Levy, J. M., Chen, P. J., Wilson, C., Newby, G. A., Raguram, A., & Liu, D. R.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Liu, David R.
- ORCID
- Venue
- Nature
- Published
- 2019-10-21
- Volume
- 576
- Issue
- 7785
- Pages
- 149-157
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6907074
- OpenAlex
- W2981137429
- Cited by
- 4,767
- References
- 49
- Citations by year
- 2026: 715 · 2025: 778 · 2024: 712 · 2023: 680 · 2022: 698 · 2021: 629 · 2020: 514 · 2019: 37 · 2014: 1
- FWCI
- 155.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RM1HG009490)
- National Institute of General Medical Sciences (T32GM095450, R35GM118062)
- National Institute of Allergy and Infectious Diseases (U01AI142756)
- National Institute of Biomedical Imaging and Bioengineering (R01EB022376)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- prime editing, genome editing, Cas9 endonuclease, reverse transcriptase, sickle cell disease, Tay-Sachs disease, HBB mutations, point mutation correction, off-target editing, homology-directed repair, base editing, disease-associated mutations, human cells
- MeSH terms
- Gene Editing, Cell Line, DNA, Humans, Saccharomyces cerevisiae, Genome, Point Mutation, DNA Breaks, Double-Stranded
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