Variability in genome editing outcomes: challenges for research reproducibility and clinical safety

Abstract Genome editing tools have already revolutionised biomedical research and are also expected to have an important impact in the clinic. However, their extensive use in research has revealed much unpredictability, both off- and on-target, in the outcome of their application. We discuss the challenges associated with this unpredictability, both for research and in the clinic. For the former, an extensive validation of the model is essential. For the latter, potential unpredicted activity does not preclude the use of these tools but requires that molecular evidence to underpin the relevant risk:benefit evaluation is available. Safe and successful clinical application will also depend on the mode of delivery and the cellular context.