The hidden risks of CRISPR/Cas: structural variations and genome integrity

Clotilde Aussel, Toni Cathomen () and Carla Fuster-García
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Clotilde Aussel: Medical Center – University of Freiburg
Toni Cathomen: Medical Center – University of Freiburg
Carla Fuster-García: Medical Center – University of Freiburg

Nature Communications, 2025, vol. 16, issue 1, 1-5

Abstract: Abstract CRISPR/Cas technology has revolutionized genome engineering, unlocking unprecedented therapeutic potential. However, beyond well-documented concerns of off-target (OT) mutagenesis, recent studies reveal a more pressing challenge: large structural variations (SVs), including chromosomal translocations and megabase-scale deletions, particularly in cells treated with DNA-PKcs inhibitors. These undervalued genomic alterations raise substantial safety concerns for clinical translation. As more CRISPR-based therapies progress toward the clinic, understanding and mitigating these risks is paramount. Here, we review emerging evidence on on-target aberrations and chromosomal translocations, identify key gaps in our understanding of the DNA repair pathways underlying these adverse effects, and discuss strategies to improve the safety of genome editing.

Date: 2025
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DOI: 10.1038/s41467-025-62606-z

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