CRISPR/Cas9-mediated gene editing. A promising strategy in hematological disorders

Ugalde, Laura; Fañanas, Sara; Torres, Raúl; Quintana-Bustamante, Óscar; Rı́o, Paula

doi:10.1016/j.jcyt.2022.11.014

Cited by 4 publications

(1 citation statement)

References 86 publications

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“…In recent years, transplantation of genetically modified autologous hematopoietic stem and progenitor cells (HSPCs) has provided clinical benefit in subjects with inherited hematological and immunological disorders. Transfer of a therapeutic gene to HSPCs has been successfully achieved using replication-defective integrating lentiviral vectors [1][2][3][4][5][6] and, more recently, the programmable CRISPR-Cas9 nuclease system for precise genome editing [7][8][9] . The RNA-guided (gRNA) Cas9 nuclease induces site-specific DNA double-stranded breaks (DSBs) within the genome of target HSPCs, triggering transient activation of p53-mediated DNA damage response (DDR) and cell cycle arrest to enable DNA repair.…”

Section: Mainmentioning

confidence: 99%

Post-Transplant Administration of G-CSF Impedes Engraftment of Gene Edited Human Hematopoietic Stem Cells by Exacerbating the p53-Mediated DNA Damage Response

Araki

Chen

Redekar

et al. 2023

Preprint

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Granulocyte colony stimulating factor (G-CSF) is commonly used as adjunct treatment to hasten recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, the utility of G-CSF administration after ex vivo gene therapy procedures targeting human HSPCs has not been thoroughly evaluated. Here, we provide evidence that post-transplant administration of G-CSF impedes engraftment of CRISPR-Cas9 gene edited human HSPCs in xenograft models. G-CSF acts by exacerbating the p53-mediated DNA damage response triggered by Cas9-mediated DNA double-stranded breaks. Transient p53 inhibition in culture attenuates the negative impact of G-CSF on gene edited HSPC function. In contrast, post-transplant administration of G-CSF does not impair the repopulating properties of unmanipulated human HSPCs or HSPCs genetically engineered by transduction with lentiviral vectors. The potential for post-transplant G-CSF administration to aggravate HSPC toxicity associated with CRISPR-Cas9 gene editing Cas9 should be considered in the design of ex vivo autologous HSPC gene editing clinical trials.

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