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Nat Commun ; 15(1): 4965, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862518

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 ß-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.


Subject(s)
Anemia, Sickle Cell , Gene Editing , Genetic Therapy , Hematopoietic Stem Cells , Transcription Activator-Like Effector Nucleases , Anemia, Sickle Cell/therapy , Anemia, Sickle Cell/genetics , Gene Editing/methods , Animals , Hematopoietic Stem Cells/metabolism , Humans , Female , Mice , Genetic Therapy/methods , Transcription Activator-Like Effector Nucleases/metabolism , Transcription Activator-Like Effector Nucleases/genetics , Hematopoietic Stem Cell Transplantation , beta-Globins/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , DNA Repair , Mutation , beta-Thalassemia/therapy , beta-Thalassemia/genetics , Disease Models, Animal , Gene Transfer Techniques
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