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

Rajeev Rai, Marianna Romito, Elizabeth Rivers, Giandomenico Turchiano, Georges Blattner, Winston Vetharoy, Dariusz Ladon, Geoffroy Andrieux, Fang Zhang, Marta Zinicola, Diego Leon-Rico, Giorgia Santilli, Adrian J. Thrasher and Alessia Cavazza ()
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Rajeev Rai: University College London
Marianna Romito: University College London
Elizabeth Rivers: University College London
Giandomenico Turchiano: University College London
Georges Blattner: University College London
Winston Vetharoy: University College London
Dariusz Ladon: SIHMDS-Acquired Genomics, Great Ormond Street Hospital for Children NHS Foundation Trust
Geoffroy Andrieux: University of Freiburg
Fang Zhang: University College London
Marta Zinicola: University College London
Diego Leon-Rico: University College London
Giorgia Santilli: University College London
Adrian J. Thrasher: University College London
Alessia Cavazza: University College London

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17626-2

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