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

Arianna Moiani (), Gil Letort, Sabrina Lizot, Anne Chalumeau, Chloe Foray, Tristan Felix, Diane 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 and Julien Valton ()
Additional contact information
Arianna Moiani: Cellectis S.A.
Gil Letort: Cellectis S.A.
Sabrina Lizot: Cellectis S.A.
Anne Chalumeau: INSERM UMR 1163
Chloe Foray: Cellectis S.A.
Tristan Felix: INSERM UMR 1163
Diane Clerre: Cellectis S.A.
Sonal Temburni-Blake: Cellectis Inc.
Patrick Hong: Cellectis Inc.
Sophie Leduc: Cellectis S.A.
Noemie Pinard: Cellectis S.A.
Alan Marechal: Cellectis S.A.
Eduardo Seclen: Cellectis Inc.
Alex Boyne: Cellectis Inc.
Louisa Mayer: Cellectis Inc.
Robert Hong: Cellectis Inc.
Sylvain Pulicani: Cellectis S.A.
Roman Galetto: Cellectis S.A.
Agnès Gouble: Cellectis S.A.
Marina Cavazzana: Assistance Publique Hopitaux de Paris
Alexandre Juillerat: Cellectis Inc.
Annarita Miccio: INSERM UMR 1163
Aymeric Duclert: Cellectis S.A.
Philippe Duchateau: Cellectis S.A.
Julien Valton: Cellectis S.A.

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49353-3

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