Muñoz, P;
Tristán-Manzano, M;
Sánchez-Gilabert, A;
Santilli, G;
Galy, A;
Thrasher, AJ;
Martin, F;
(2020)
WAS-promoter driven lentiviral vectors mimic closely the lop-sided WASP expression during megakaryocytic differentiation: a comparative study.
Molecular Therapy - Methods & Clinical Development
10.1016/j.omtm.2020.09.006.
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Abstract
Transplant of gene-modified autologous hematopoietic progenitors cells has emerged as a new therapeutic approach for Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency with microthrombocytopenia and abnormal lymphoid and myeloid functions. In spite of the clinical benefit obtained in the ongoing clinical trials, platelet restoration is suboptimal. The incomplete restoration of platelets in these patients can be explained either by a low number of corrected cells or by insufficient or inadequate WASP expression during megakaryocyte differentiation and/or in platelets. We therefore used in vitro models to study the endogenous WASP expression pattern during megakaryocytic differentiation and compared it with the expression profiles achieved by different therapeutic lentiviral vectors (LVs) driving WAS cDNA through different regions of WAS promoter. Our data showed that all WAS-promoter driven LVs mimic very closely the endogenous WAS expression kinetic during megakaryocytic differentiation. However, LVs harbouring the full-length WAS-proximal promoter (WW1.6) or a combination of the WAS alternative and proximal promoters (AW) had the best behaviour. Finally, all WAS-driven LVs restored WAS knockout (WASKO) mice phenotype and functional defects of hematopoietic stem progenitor cells (HSPCs) from a WAS patient with similar efficiency. In summary, our data back up the use of WW1.6 and AW LVs as physiological gene transfer tools for WAS therapy.
| Type: | Article |
|---|---|
| Title: | WAS-promoter driven lentiviral vectors mimic closely the lop-sided WASP expression during megakaryocytic differentiation: a comparative study |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.omtm.2020.09.006 |
| Publisher version: | https://doi.org/10.1016/j.omtm.2020.09.006 |
| 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: | Wiskott-Aldrich syndrome (WAS), alternative WAS promoter, mouse model, hematopoietic stem progenitor cells (HSPCs), WAS knockout (WASKO), cellular models, megakaryocytic differentiation, lentiviral vectors, phenotypic rescue, WAS patients |
| 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/10110891 |
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