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Why can off-target DNA changes be a safety concern in CRISPR-based treatments?

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A step-by-step diagram shows donor DNA and vector DNA cut with restriction enzymes to create overhangs, mixed and sealed with ligase to form recombinant DNA, which is introduced into bacterial cells. The recombinant DNA replicates as the cells divide, producing clones. — biotechnology Steps involved in the engineering of a recombinant DNA molecule.

In the context of biotechnology, off-target DNA changes are a significant safety concern because they represent unintended genetic alterations that occur when the CRISPR system acts on sequences other than the intended target.1

Because the precision of gene editing relies on the guide RNA binding to a specific DNA sequence, there is a risk that the nuclease may catalyze a double-stranded break at an incorrect location within the genome. These unwanted modifications can potentially introduce new genetic errors or mutations, which may have unforeseen and harmful biological consequences for the patient.12

Ethically, researchers emphasize that because there remain many unknowns regarding the long-term effects of these technologies, there is a moral imperative to ensure safety and minimize the risk of introducing unintended genetic damage while attempting to correct existing defects. Consequently, ongoing clinical investigations are focused on better understanding how these CRISPR-induced alterations affect cells and how to mitigate the risks associated with off-target activity.12