{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:12:58Z","timestamp":1792141978458,"version":"4.4.0"},"reference-count":67,"publisher":"American Society of Hematology","issue":"8","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,20]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Successful transplantation of autologous gene-modified hematopoietic stem and progenitor cells (HSPCs) requires efficient ablation of resident hematopoietic stem cells. Considering that conventional myeloablative conditioning regimens are associated with nonhematologic toxicities, we evaluated CD45-directed radioimmunotherapy (RIT) using the \u03b1-emitter astatine 211 (211At) before the transplantation of ex vivo gene-edited autologous HSPCs in nonhuman primates as an alternative. We humanized the CD45 antibody, BC8, and labeled it with 211At. As a model, mobilized CD34+ HSPCs were multiplex gene-edited using an adenine base editor, modifying the HBG promoter to reactivate fetal hemoglobin and deleting CD33. Two animals each received 300 or 400 \u03bcCi\/kg of 211At. In contrast to historic controls conditioned with total body irradiation, CD45-RIT animals did not show any noticeable nonhematopoietic toxicities and were almost entirely transfusion independent with rapid recovery of neutrophils and platelets. Dose-dependent engraftment of gene-edited cells was enabled by 211At. A new single-cell sequencing assay revealed up to 70% combined monoallelic and biallelic gene-editing efficiency in the blood, consistent with complete replacement of the bone marrow stem cell compartment. Assessment by bulk analysis underestimated the frequency of gene-edited cells, highlighting the importance of a single-cell readout. Single-cell sequencing further confirmed stable and unbiased contribution of multiplex-edited HSPCs to all mature lineages in the blood, providing high-resolution data assuring successful replacement upon autologous HSPC gene therapy. The levels of edited cells remained stable for the entire follow-up of &amp;gt;18 months. Collectively, these studies identify 211At-CD45 RIT as a targeted alternative for myeloablative conditioning for autologous gene therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2026033789","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:01:53Z","timestamp":1780336913000},"page":"1052-1065","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":3,"title":["Astatine 211\u2013based conditioning with a humanized CD45 antibody for autologous hematopoietic stem cell gene therapy"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2842-4820","authenticated-orcid":false,"given":"Stefan","family":"Radtke","sequence":"first","affiliation":[{"name":"1Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"2Division of Hematology & Medical Oncology, Department of Medicine, University of Washington, 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