Rai, R;
Romito, M;
Rivers, E;
Turchiano, G;
Blattner, G;
Vetharoy, W;
Ladon, D;
... Cavazza, A; + view all
(2020)
Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome.
Nature Communications
, 11
(1)
, Article 4034. 10.1038/s41467-020-17626-2.
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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.
| Type: | Article |
|---|---|
| Title: | Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-020-17626-2 |
| Publisher version: | https://doi.org/10.1038/s41467-020-17626-2 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Genetic engineering, Molecular medicine, Primary immunodeficiency disorders, Stem-cell biotechnology, Targeted gene repair |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107738 |
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