2. Academic Validation
  3. Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations

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

Affiliations

  • 1 Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. gregoire.cullot@biol.ethz.ch.
  • 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. jacob.corn@biol.ethz.ch.
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.

Figures
Products