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Raffaele Telethon Institute for Gene Therapy"],"full_dataset_link":["https://www.ebi.ac.uk/ena/browser/view/PRJNA1214731"],"scientific_name":["Homo sapiens"],"tag":["xref:PubMed:40466639"],"long_description":["Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, adverse cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, limiting clinical translation. Our study uncovers a senescence-like response in genetically-engineered HSPCs triggered by p53 and IL-1/NF-κB activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways can mitigate senescence-associated responses, enhancing the repopulating capacity of edited HSPCs. Importantly, we identify Anakinra, an IL-1 signaling antagonist, as a safer and effective strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the gene-editing procedure. These findings present strategies to overcome key hurdles in HDR-based HSPC therapies, providing a framework for enhancing the efficacy and safety of these approaches in future clinical applications. Overall design: Clonal tracking by using an AAV6 repair template pool with a heritable “barcode” sequence (BAR) downstream of the GFP reporter cassette. Enhanced long-term polyclonal reconstitution of HDR-edited cells in the BM was observed for GSE56 and Anakinra treatments."],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6 mediated gene editing in hematopoietic stem cells [BAR-seq]","description":"Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6 mediated gene editing in hematopoietic stem cells [BAR-seq]","dates":{"last_updated":"2025-09-24","first_public":"2025-03-22"},"accession":"PRJNA1214731","cross_references":{"GEO":["GSE287803"],"taxon":["9606"],"PubMed":["40466639"]}}