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Significance Therapeutic genome editing has been significantly accentuated by the advent of CRISPR-based gene correction. However, genomic off-targeting has been a major setback for clinical translation. Although high-fidelity versions of Cas9 have been designed, these recognize and bind to off-targets. In this study, we characterize a naturally occurring Cas9 fromFrancisella novicida (FnCas9) that shows negligible binding affinity to off-targets differing by 1 or more mismatches, rendering it highly specific in target recognition. We show that FnCas9 can direct both homology-directed repair (HDR) and nonhomologous end-joining–mediated DNA repair, generates a higher rate of HDR and negligible off-targeting. Finally, we show its potential in therapeutic genome editing by correcting the sickle cell anemia mutation in patient-derived induced pluripotent stem cells.

Francisella novicida Cas9 interrogates genomic DNA with very high specificity and can be used for mammalian genome editing