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

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  • Clotilde Aussel

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg)

  • Toni Cathomen

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg
    Partner Site Freiburg
    University of Freiburg)

  • Carla Fuster-García

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg)

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.

Suggested Citation

  • Clotilde Aussel & Toni Cathomen & Carla Fuster-García, 2025. "The hidden risks of CRISPR/Cas: structural variations and genome integrity," Nature Communications, Nature, vol. 16(1), pages 1-5, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62606-z
    DOI: 10.1038/s41467-025-62606-z
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