Abstract:
:CRISPR-Cas genome-editing nucleases hold substantial promise for developing human therapeutic applications1-6 but identifying unwanted off-target mutations is important for clinical translation7. A well-validated method that can reliably identify off-targets in vivo has not been described to date, which means it is currently unclear whether and how frequently these mutations occur. Here we describe 'verification of in vivo off-targets' (VIVO), a highly sensitive strategy that can robustly identify the genome-wide off-target effects of CRISPR-Cas nucleases in vivo. We use VIVO and a guide RNA deliberately designed to be promiscuous to show that CRISPR-Cas nucleases can induce substantial off-target mutations in mouse livers in vivo. More importantly, we also use VIVO to show that appropriately designed guide RNAs can direct efficient in vivo editing in mouse livers with no detectable off-target mutations. VIVO provides a general strategy for defining and quantifying the off-target effects of gene-editing nucleases in whole organisms, thereby providing a blueprint to foster the development of therapeutic strategies that use in vivo gene editing.
journal_name
Naturejournal_title
Natureauthors
Akcakaya P,Bobbin ML,Guo JA,Malagon-Lopez J,Clement K,Garcia SP,Fellows MD,Porritt MJ,Firth MA,Carreras A,Baccega T,Seeliger F,Bjursell M,Tsai SQ,Nguyen NT,Nitsch R,Mayr LM,Pinello L,Bohlooly-Y M,Aryee MJ,Marescadoi
10.1038/s41586-018-0500-9subject
Has Abstractpub_date
2018-09-01 00:00:00pages
416-419issue
7723eissn
0028-0836issn
1476-4687pii
10.1038/s41586-018-0500-9journal_volume
561pub_type
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