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Biomed. Eng"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis\u2014the non-pathogenic hyper-production of red blood cells\u2014that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34\n                    <jats:sup>+<\/jats:sup>\n                    human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the\n                    <jats:italic>HBA1<\/jats:italic>\n                    gene with an\n                    <jats:italic>HBB<\/jats:italic>\n                    transgene in HSPCs (to restore normal haemoglobin production in cells with a \u03b2-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41551-024-01222-6","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T06:09:01Z","timestamp":1718604541000},"page":"1540-1552","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in haematopoietic stem and progenitor cells"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9173-9518","authenticated-orcid":false,"given":"Sofia E.","family":"Luna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-5820","authenticated-orcid":false,"given":"Joab","family":"Camarena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0084-5404","authenticated-orcid":false,"given":"Jessica P.","family":"Hampton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran R.","family":"Majeti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten T.","family":"Charlesworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Soupene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridhar","family":"Selvaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2837-2255","authenticated-orcid":false,"given":"Vivien A.","family":"Sheehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-5010","authenticated-orcid":false,"given":"M. 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M.H.P., M.K.C. and J.C. have equity in Graphite Bio. M.H.P. has equity in CRISPR Tx and serves on the board of directors of Graphite Bio and Kamau Therapeutics. J.C., M.K.C. and M.H.P. have filed provisional patent number PCT\/US2022\/077951. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}