Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells

Author:

Moiani Arianna,Letort GilORCID,Lizot Sabrina,Chalumeau AnneORCID,Foray Chloe,Felix TristanORCID,Le Clerre Diane,Temburni-Blake SonalORCID,Hong Patrick,Leduc SophieORCID,Pinard Noemie,Marechal Alan,Seclen EduardoORCID,Boyne Alex,Mayer LouisaORCID,Hong Robert,Pulicani SylvainORCID,Galetto Roman,Gouble Agnès,Cavazzana MarinaORCID,Juillerat AlexandreORCID,Miccio AnnaritaORCID,Duclert Aymeric,Duchateau PhilippeORCID,Valton JulienORCID

Abstract

AbstractSickle 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.

Publisher

Springer Science and Business Media LLC

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