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

Autor: Cullot G; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. gregoire.cullot@biol.ethz.ch., Aird EJ; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Schlapansky MF; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Yeh CD; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., van de Venn L; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Vykhlyantseva I; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Kreutzer S; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Mailänder D; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Lewków B; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Klermund J; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Montellese C; CSL Behring Research, Bern, Switzerland.; Swiss Institute for Translational Medicine sitem-insel, Bern, Switzerland., Biserni M; CSL Behring Research, Bern, Switzerland.; Swiss Institute for Translational Medicine sitem-insel, Bern, Switzerland., Aeschimann F; CSL Behring Research, Bern, Switzerland.; Swiss Institute for Translational Medicine sitem-insel, Bern, Switzerland., Vonarburg C; CSL Behring Research, Bern, Switzerland.; Swiss Institute for Translational Medicine sitem-insel, Bern, Switzerland., Gehart H; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Cathomen T; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Corn JE; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. jacob.corn@biol.ethz.ch.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Nov 27. Date of Electronic Publication: 2024 Nov 27.
DOI: 10.1038/s41587-024-02488-6
Abstrakt: 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.
Competing Interests: Competing interests: J.E.C. is a co-founder and scientific advisory board (SAB) member of Spotlight Therapeutics and Serac Biosciences and an SAB member of Mission Therapeutics, Relation Therapeutics, Hornet Bio, Kano Therapeutics and the Joint AstraZeneca–CRUK Functional Genomics Centre. The laboratory of J.E.C. has funded collaborations with Allogene, Cimeio, CSL Behring and Serac. None of these collaborations is related to this paper. T.C. is an advisor to Cimeio Therapeutics, Excision BioTherapeutics, GenCC and Novo Nordisk. T.C. has sponsored research collaborations with Cellectis. T.C. holds a patent on CAST-seq (US11319580B2). F.A., C.M., M.B. and C.V. are employees of CSL Behring AG. The other authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: