Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome.

Autor:	Rai R; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Romito M; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Rivers E; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Turchiano G; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Blattner G; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Vetharoy W; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Ladon D; SIHMDS-Acquired Genomics, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK., Andrieux G; Institute of Medical Bioinformatics and System Medicine, University of Freiburg, 26 Stefan-Meier-Strasse, 79104, Freiburg, Germany., Zhang F; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Zinicola M; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Leon-Rico D; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Santilli G; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Thrasher AJ; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Cavazza A; Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK. a.cavazza@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Aug 12; Vol. 11 (1), pp. 4034. Date of Electronic Publication: 2020 Aug 12.
DOI:	10.1038/s41467-020-17626-2
Abstrakt:	Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.
Databáze:	MEDLINE
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