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Search-and-replace genome editing without double-strand breaks or donor DNA

Nature (London), 2019-12, Vol.576 (7785), p.149-157 [Peer Reviewed Journal]

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Dec 5, 2019 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-019-1711-4 ;PMID: 31634902

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Title:
Search-and-replace genome editing without double-strand breaks or donor DNA
Author: Anzalone, Andrew V ; Randolph, Peyton B ; Davis, Jessie R ; Sousa, Alexander A ; Koblan, Luke W ; Levy, Jonathan M ; Chen, Peter J ; Wilson, Christopher ; Newby, Gregory A ; Raguram, Aditya ; Liu, David R
Subjects: Analysis ; Binding sites ; Byproducts ; Cell Line ; Cell lines ; Clonal deletion ; CRISPR ; Deoxyribonucleic acid ; DNA ; DNA - genetics ; DNA Breaks, Double-Stranded ; DNA damage ; DNA repair ; Donation of organs, tissues, etc ; Editing ; Efficiency ; Endonuclease ; Epitopes ; Gene Editing ; Genetic aspects ; Genetic variance ; Genome ; Genomes ; Homology ; Humans ; Kinases ; Mutation ; Neurological diseases ; Nuclease ; Point Mutation ; Proteins ; Ribonucleic acid ; RNA ; RNA editing ; RNA-directed DNA polymerase ; Saccharomyces cerevisiae ; Sickle cell disease ; Structure ; Tay-Sachs disease ; Transversion
Is Part Of: Nature (London), 2019-12, Vol.576 (7785), p.149-157
Description: Most genetic variants that contribute to disease are challenging to correct efficiently and without excess byproducts . 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.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/s41586-019-1711-4
PMID: 31634902
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
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Search-and-replace genome editing without double-strand breaks or donor DNA

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Dec 5, 2019 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-019-1711-4 ;PMID: 31634902

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