{"id":"doi:10.1038/s41551-023-01026-0","kind":"article","title":"Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice","authors":["Everette KA","Newby GA","Levine RM","Mayberry K","Jang Y","Mayuranathan T","Nimmagadda N","Dempsey E","Li Y","Bhoopalan SV","Liu X","Davis JR","Nelson AT","Chen PJ","Sousa AA","Cheng Y","Tisdale JF","Weiss MJ","Yen JS","Liu DR"],"author_count":20,"year":2023,"published":"2023-04-17","venue":"Nature biomedical engineering","cited_by":132,"doi":"10.1038/s41551-023-01026-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41551-023-01026-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41551-023-01026-0","updated":null,"pmid":"37069266","pmcid":"PMC10195679","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10195679/pdf","abstract":"Sickle-cell disease (SCD) is caused by an A·T-to-T·A transversion mutation in the β-globin gene (HBB). Here we show that prime editing can correct the SCD allele (HBB S ) to wild type (HBB A ) at frequencies of 15%-41% in haematopoietic stem and progenitor cells (HSPCs) from patients with SCD. Seventeen weeks after transplantation into immunodeficient mice, prime-edited SCD HSPCs maintained HBB A levels and displayed engraftment frequencies, haematopoietic differentiation and lineage maturation similar to those of unedited HSPCs from healthy donors. An average of 42% of human erythroblasts and reticulocytes isolated 17 weeks after transplantation of prime-edited HSPCs from four SCD patient donors expressed HBB A , exceeding the levels predicted for therapeutic benefit. HSPC-derived erythrocytes carried less sickle haemoglobin, contained HBB A -derived adult haemoglobin at 28%-43% of normal levels and resisted hypoxia-induced sickling. Minimal off-target editing was detected at over 100 sites nominated experimentally via unbiased genome-wide analysis. Our findings support the feasibility of a one-time prime editing SCD treatment that corrects HBB S to HBB A , does not require any viral or non-viral DNA template and minimizes undesired consequences of DNA double-strand breaks.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice\" by Everette KA, Newby GA, Levine RM et al., https://doi.org/10.1038/s41551-023-01026-0, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}