{"id":"doi:10.1038/s41467-023-41153-5","kind":"article","title":"Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model","authors":["Uchida N","Stasula U","Demirci S","Germino-Watnick P","Hinds M","Le A","Chu R","Berg A","Liu X","Su L","Wu X","Krouse AE","Linde NS","Bonifacino A","Hong SG","Dunbar CE","Lanieri L","Bhat A","Palchaudhuri R","Bennet B","Hoban M","Bertelsen K","Olson LM","Donahue RE","Tisdale JF"],"author_count":25,"year":2023,"published":"2023-10-12","venue":"Nature communications","cited_by":50,"doi":"10.1038/s41467-023-41153-5","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-023-41153-5","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-023-41153-5","updated":null,"pmid":"37828021","pmcid":"PMC10570335","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10570335/pdf","abstract":"Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.","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 \"Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model\" by Uchida N, Stasula U, Demirci S et al., https://doi.org/10.1038/s41467-023-41153-5, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}