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. 2024 Nov 27.
doi: 10.1038/s41587-024-02488-6. Online ahead of print.

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

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

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

Grégoire Cullot et al. Nat Biotechnol. .

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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Conflict of interest statement

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.

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