Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations

  • Nat Biotechnol. 2024 Nov 27. doi: 10.1038/s41587-024-02488-6.
Grégoire Cullot  1 ,  Eric J Aird  2 ,  Moritz F Schlapansky  2 ,  Charles D Yeh  2 ,  Lilly van de Venn  2 ,  Iryna Vykhlyantseva  2 ,  Susanne Kreutzer  2 ,  Dominic Mailänder  2 ,  Bohdan Lewków  2 ,  Julia Klermund  3  4 ,  Christian Montellese  5  6 ,  Martina Biserni  5  6 ,  Florian Aeschimann  5  6 ,  Cédric Vonarburg  5  6 ,  Helmuth Gehart  2 ,  Toni Cathomen  3  4 ,  Jacob E Corn  7
Affiliations
  • 1. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. [email protected].
  • 2. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
  • 3. Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
  • 4. Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 5. CSL Behring Research, Bern, Switzerland.
  • 6. Swiss Institute for Translational Medicine sitem-insel, Bern, Switzerland.
  • 7. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. [email protected].
PMID: 39604565 DOI: 10.1038/s41587-024-02488-6
Abstract

The DNA-PKcs inhibitor AZD7648 enhances CRISPR-Cas9-directed homology-directed repair efficiencies, with potential for clinical utility, but its possible on-target consequences are unknown. We found that genome editing with AZD7648 causes frequent kilobase-scale and megabase-scale deletions, chromosome arm loss and translocations. These large-scale chromosomal alterations evade detection through typical genome editing assays, prompting caution in deploying AZD7648 and reinforcing the need to investigate multiple types of potential editing outcomes.

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