Diez, B;
Genovese, P;
Roman-Rodriguez, FJ;
Alvarez, L;
Schiroli, G;
Ugalde, L;
Rodriguez-Perales, S;
... Rio, P; + view all
(2017)
Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients.
EMBO Molecular Medicine
, 9
(11)
pp. 1574-1588.
10.15252/emmm.201707540.
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Abstract
Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34+ cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34+ cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells.
| Type: | Article |
|---|---|
| Title: | Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.201707540 |
| Publisher version: | https://doi.org/10.15252/emmm.201707540 |
| 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: | CD34+ cells, Fanconi anemia, gene editing, hematopoietic stem and progenitor cells, zinc finger nucleases, Animals, Antigens, CD34, Base Sequence, Cells, Cultured, Dependovirus, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Fetal Blood, Gene Editing, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Reactive Oxygen Species, Zinc Finger Nucleases |
| 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/10126603 |
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