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.

Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome / Rai, R.; Romito, M.; Rivers, E.; Turchiano, G.; Blattner, G.; Vetharoy, W.; Ladon, D.; Andrieux, G.; Zhang, F.; Zinicola, M.; Leon-Rico, D.; Santilli, G.; Thrasher, A. J.; Cavazza, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), pp. 1-2. [10.1038/s41467-020-17626-2]

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

Turchiano G.;Cavazza A.
2020

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.
2020
11
1
1
2
Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome / Rai, R.; Romito, M.; Rivers, E.; Turchiano, G.; Blattner, G.; Vetharoy, W.; Ladon, D.; Andrieux, G.; Zhang, F.; Zinicola, M.; Leon-Rico, D.; Santilli, G.; Thrasher, A. J.; Cavazza, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), pp. 1-2. [10.1038/s41467-020-17626-2]
Rai, R.; Romito, M.; Rivers, E.; Turchiano, G.; Blattner, G.; Vetharoy, W.; Ladon, D.; Andrieux, G.; Zhang, F.; Zinicola, M.; Leon-Rico, D.; Santilli, G.; Thrasher, A. J.; Cavazza, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1327205
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