Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.06.29.547089v1?rss=1

Authors: Araki, D., Chen, V., Redekar, N., Salisbury-Ruf, C., Luo, Y., Liu, P., Li, Y., Smith, R., Dagur, P., Combs, C., Larochelle, A.

Abstract:
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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