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Why can unwanted off-target DNA changes be a risk of CRISPR gene editing?

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CRISPR-Cas9; gene editing — gene editing The CRISPR-Cas9 gene-editing complex from the bacterium *Streptococcus pyogenes*.

Off-target DNA changes in CRISPR gene editing occur when the system’s nuclease—such as Cas9—cleaves the DNA at unintended locations within the genome rather than at the specific, desired target site.12

This risk arises because the guide RNA used to direct the nuclease may occasionally bind to DNA sequences that are similar, but not identical, to the intended target. When this happens, the nuclease may catalyze a double-stranded break at these off-target sites, potentially introducing unwanted genetic mutations.12

These unintended alterations are a significant safety concern because they can disrupt functional genes or otherwise interfere with normal cellular processes. Consequently, researchers are actively investigating these risks to improve the precision of gene-editing technologies and ensure that interventions do not inadvertently introduce as many genetic errors as they aim to correct. Ensuring the safety and accuracy of these tools is a fundamental ethical imperative in the development of gene therapy and other genetic applications.231