| Autor: |
Naoya Uchida, Ulana Stasula, Selami Demirci, Paula Germino-Watnick, Malikiya Hinds, Anh Le, Rebecca Chu, Alexander Berg, Xiong Liu, Ling Su, Xiaolin Wu, Allen E. Krouse, N. Seth Linde, Aylin Bonifacino, So Gun Hong, Cynthia E. Dunbar, Leanne Lanieri, Anjali Bhat, Rahul Palchaudhuri, Bindu Bennet, Megan Hoban, Kirk Bertelsen, Lisa M. Olson, Robert E. Donahue, John F. Tisdale |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-11 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-41153-5 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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