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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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.
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.
Park, S. H. et al. Comprehensive analysis and accurate quantification of unintended large gene modifications induced by CRISPR-Cas9 gene editing. Sci. Adv. 8, eabo7676 (2022). This paper reports a comprehensive characterization of the unintended editing outcomes occurring at CRISPR–Cas9 target sites in HSPCs.
Everette, K. A. et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat. Biomed. Eng. 7, 616–628 (2023). This paper reports ex vivo prime editing in human HSPCs for the treatment of sickle cell disease.
Zeng, J. et al. Therapeutic base editing of human hematopoietic stem cells. Nat. Med. 26, 535–541 (2020). This paper reports ex vivo base editing in human HSPCs for the treatment of hemoglobinopathies.
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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 (2023). https://doi.org/10.1038/s41587-023-01916-3