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Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells.
Moiani, Arianna; Letort, Gil; Lizot, Sabrina; Chalumeau, Anne; Foray, Chloe; Felix, Tristan; Le Clerre, Diane; Temburni-Blake, Sonal; Hong, Patrick; Leduc, Sophie; Pinard, Noemie; Marechal, Alan; Seclen, Eduardo; Boyne, Alex; Mayer, Louisa; Hong, Robert; Pulicani, Sylvain; Galetto, Roman; Gouble, Agnès; Cavazzana, Marina; Juillerat, Alexandre; Miccio, Annarita; Duclert, Aymeric; Duchateau, Philippe; Valton, Julien.
Afiliación
  • Moiani A; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France. arianna.moiani@cellectis.com.
  • Letort G; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Lizot S; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Chalumeau A; Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France.
  • Foray C; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Felix T; Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France.
  • Le Clerre D; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Temburni-Blake S; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Hong P; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Leduc S; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Pinard N; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Marechal A; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Seclen E; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Boyne A; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Mayer L; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Hong R; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Pulicani S; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Galetto R; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Gouble A; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
  • Cavazzana M; Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique Hopitaux de Paris, Paris, France.
  • Juillerat A; Human Lymphohematopoiesis Laboratory, Imagine Institute, INSERM UMR1163, Paris Cité University, Paris, France.
  • Miccio A; Biotherapy Department, Necker Children's Hospital, Assistance Publique Hopitaux de Paris, Paris, France.
  • Duclert A; Cellectis Inc., 430 East 29th Street, New York, NY, USA.
  • Duchateau P; Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France.
  • Valton J; Cellectis S.A., 8 Rue de la Croix Jarry, Paris, France.
Nat Commun ; 15(1): 4965, 2024 Jun 11.
Article en En | 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Terapia Genética / Nucleasas de los Efectores Tipo Activadores de la Transcripción / Edición Génica / Anemia de Células Falciformes Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Terapia Genética / Nucleasas de los Efectores Tipo Activadores de la Transcripción / Edición Génica / Anemia de Células Falciformes Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido