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• W3091100833 abstract "Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy." @default.
• W3091100833 created "2020-10-08" @default.
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• W3091100833 date "2020-09-29" @default.
• W3091100833 modified "2023-10-14" @default.
• W3091100833 title "Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment" @default.
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• W3091100833 doi "https://doi.org/10.3390/cells9102194" @default.
• W3091100833 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7600420" @default.
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