Journal Article Review Epublish
PubMed: 40764301 DOI: 10.1038/s41467-025-62606-z
The hidden risks of CRISPR/Cas: structural variations and genome integrity.
Nat Commun 16(1):7208
Authors: Clotilde Aussel, Toni Cathomen, Carla Fuster-García
Affiliations
- Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
- Center for Cell and Gene Therapy Freiburg (CGF), Medical Center - University of Freiburg, Freiburg, Germany.
- Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
- Center for Cell and Gene Therapy Freiburg (CGF), Medical Center - University of Freiburg, Freiburg, Germany.
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany.
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
MeSH
Clustered Regularly Interspaced Short Palindromic Repeats, Safety, Translocation, Genetic, Genome, Therapeutics