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Genotoxicity concerns for base and prime editors in hematopoietic stem cells

Although base and prime editors can be highly efficient in human hematopoietic stem cells, we find they can cause adverse cellular responses, including reduced engraftment and the generation of DNA double-strand breaks and genotoxic byproducts, albeit at a lower frequency than Cas9. We also find that base editors increase the genome-wide mutagenic load.

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Fig. 1: Multiparameter comparison of Cas9, BE and PE for editing HSPCs in vitro and in xenografts.

References

  1. Anzalone, A. V. et al. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 38, 824–844 (2020). This review presents the different editing systems.

  2. Ferrari, S. et al. Efficient gene editing of human long-term hematopoietic stem cells validated by clonal tracking. Nat Biotechnol. 38, 1298–1308 (2020). This paper reports the effect of Cas9-induced p53 activation on engraftment capacity of human HSPCs and graft clonality.

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This is a summary of: Fiumara, M. et al. Genotoxic effects of base and prime editing in human hematopoietic stem cells. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01915-4 (2023).

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Genotoxicity concerns for base and prime editors in hematopoietic stem cells. Nat Biotechnol 42, 850–851 (2024). https://doi.org/10.1038/s41587-023-01916-3

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