Prime Editing is a next-generation gene editing technology that acts like a DNA word processor, with the power to search and replace genetic sequences at their exact location in the genome, all without making double-strand breaks in DNA.
How Prime Editing Works
Programmable for both search & replace
Exemplary Prime Editing process using Cas and RT. Abbreviations: pegRNA = Prime Editing guide RNA; RT = reverse transcriptase; Cas = CRISPR associated protein
- Programmable and highly flexible
- High fidelity and specificity
- High editing efficiency
- Minimal off-target activity
- Potential for improved gene function through in situ editing
- Edits in multiple clinically relevant rapidly dividing, non-dividing, mammalian, non-mammalian cell types and organs
- No DNA double-strand breaks
- Validated by multiple independent research laboratories worldwide
prime editing can correct all different types of mutations
Convert any base pair into any other
Mutated base pairs can be substituted
Extra base pairs can be removed
Missing base pairs can be inserted
Prime Editing can correct almost all types of gene mutations and can be used to modify gene-regulatory sequences. These edits can be made in therapeutically relevant cells and organs, including specialized terminally-differentiated cells. A single Prime Editor can correct the individual mutations found across patients, meaning that Prime Editing can potentially address approximately 90% of known disease-causing genetic mutations.
one prime editing pegRNA can precisely correct the individual mutations found across many patients
Abbreviations: pegRNA = Prime Editing guide RNA.
Prime Editing occurs with high fidelity, making the correct edit at the exact target site with minimal off-target activity. Prime Editing does not cause double-strand breaks and does not affect cell viability, which may contribute to better patient outcomes, fewer side effects and overall improved safety.
prime editing corrections occur at the natural place in the genome and are permanent
Prime Editing makes a permanent correction at the natural place in the genome. As a result, the corrected gene returns to physiologic regulation. This can be especially important where gene dosage is critical to protein function. Other approaches may not faithfully restore gene function. These advantages can provide patients with long-lasting benefit, complete correction and a durable cure.
prime editing can be delivered to the right place in the body using multiple modalities
Prime-Edited cell therapy
Prime Editing can be delivered via multiple modalities including RNA, DNA, and RNA–protein complexes, unlocking opportunities for genetic medicine. By taking advantage of proven delivery technologies, we can choose the best method to deliver Prime Editing depending on where it needs to go in the body. This flexibility provides opportunities to fix the underlying causes of genetic disorders, treat common diseases, and target cancers with treatments that are easily distributed, manufactured at scale, and re-dosed if necessary.
Programmable large DNA deletion, replacement, integration, and inversion with twin prime editing and site-specific recombinases
Andrew V. Anzalone, Xin D. Gao, Christopher J. Podracky, Andrew T. Nelson, Luke W. Koblan, Aditya Raguram, Jonathan M. Levy, Jaron A.M. Mercer & David R. Liu
Engineered pegRNAs improve prime editing efficiency
James W. Nelson, Peyton B. Randolph, Simon P. Shen, Kelcee A. Everette, Peter J. Chen, Andrew V. Anzalone, Meirui An, Gregory A. Newby, Jonathan C. Chen, Alvin Hsu & David R. Liu
- Prime editing for functional repair in patient-derived disease models. Schene, I.F., Joore, I.P., Oka, R. et al. Nat Commun 11, 5352 (2020).
- Efficient generation of mouse models with the prime editing system. Liu, Y., Li, X., He, S. et al. Cell Discov 6, 27 (2020).
- Unbiased investigation of specificities of prime editing systems in human cells. Kim, D.Y., Moon, S.B., Ko, J.-H., et al. Nucleic Acids Res 48, 10576–10589 (2020).
- Predicting the efficiency of prime editing guide RNAs in human cells. Kim, H.K., Yu, G., Park, J. et al. Nat Biotechnol 39, 198–206 (2021).
- PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Hsu, J.Y., Grünewald, J., Szalay, R. et al. Nat Commun 12, 1034 (2021).
- Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice. Liu, P., Liang, SQ., Zheng, C. et al. Nat Commun 12, 2121 (2021).
- Genome-wide specificity of prime editors in plants. Jin, S., Lin, Q., Luo, Y. et al. Nat Biotechnol (2021).
- Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression. Gao, P., Lyu, Q., Ghanam, A.R. et al. Genome Biol 22, 83 (2021).
- Engineered prime editors with PAM flexibility. Kweon, J., Yoon, J.-K., Jang, A.-H., et al. Mol. Ther. 29, 2001-7 (2021).
- Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Chen, P., Hussmann, J., Yan, J., Weissman, J, Adamson, B., Liu, D. et al Cell. 2021 Oct 28 (2021)
- Targeted mutagenesis in mouse cells and embryos using an enhanced prime editor. Park, SJ., Jeong, T.Y., Shin, S.K. et al. Genome Biol 22, 170 (2021).
- High-efficiency prime editing with optimized, paired pegRNAs in plants. Lin, Q., Jin, S., Zong, Y. et al. Nat Biotechnol 39, 923–927 (2021).
- Precise genomic deletions using paired prime editing. Choi J, Chen W, Suiter CC, et al. Nat Biotechnol (2021).
- Increasing the efficiency and precision of prime editing with guide RNA pairs. Zhuang, Y., Liu, J., Wu, H. et al. Nat Chem Biol (2021).
- Deletion and replacement of long genomic sequences using prime editing. Jiang, T., Zhang, XO., Weng, Z. et al. Nat Biotechnol (2021).
- Application of prime editing to the correction of mutations and phenotypes in adult mice with liver and eye diseases. Jang, H., Jo, D.H., Cho, C.S. et al. Nat Biomed Eng (2021).
- Enhanced prime editing systems by manipulating cellular determinants of editing outcomes, Chen, P.J., Hussmann, J.A., Yan, J. et al. Cell 184, 5635-5652.e29 (2021).
- Broadening the reach and investigating the potential of prime editors through fully viral gene deleted adenoviral vector delivery. Wang, Q., Liu, J., Janssen, J.M., et al. Nucleic Acids Res gkab938 (2021).