| Autor: |
Arianna Moiani, Gil Letort, Sabrina Lizot, Anne Chalumeau, Chloe Foray, Tristan Felix, Diane Le Clerre, Sonal Temburni-Blake, Patrick Hong, Sophie Leduc, Noemie Pinard, Alan Marechal, Eduardo Seclen, Alex Boyne, Louisa Mayer, Robert Hong, Sylvain Pulicani, Roman Galetto, Agnès Gouble, Marina Cavazzana, Alexandre Juillerat, Annarita Miccio, Aymeric Duclert, Philippe Duchateau, Julien Valton |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-21 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-49353-3 |
| Popis: |
Abstract Sickle cell disease is a devastating blood disorder that originates from a single point mutation in the HBB gene coding for hemoglobin. Here, we develop a GMP-compatible TALEN-mediated gene editing process enabling efficient HBB correction via a DNA repair template while minimizing risks associated with HBB inactivation. Comparing viral versus non-viral DNA repair template delivery in hematopoietic stem and progenitor cells in vitro, both strategies achieve comparable HBB correction and result in over 50% expression of normal adult hemoglobin in red blood cells without inducing β-thalassemic phenotype. In an immunodeficient female mouse model, transplanted cells edited with the non-viral strategy exhibit higher engraftment and gene correction levels compared to those edited with the viral strategy. Transcriptomic analysis reveals that non-viral DNA repair template delivery mitigates P53-mediated toxicity and preserves high levels of long-term hematopoietic stem cells. This work paves the way for TALEN-based autologous gene therapy for sickle cell disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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