TY - JOUR
T1 - Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients
AU - Río, Paula
AU - Navarro, Susana
AU - Guenechea, Guillermo
AU - Sánchez-Domínguez, Rebeca
AU - Lamana, Maria Luisa
AU - Yañez, Rosa
AU - Casado, Jose A.
AU - Mehta, Parinda A.
AU - Pujol, Maria Roser
AU - Surrallés, Jordi
AU - Charrier, Sabine
AU - Galy, Anne
AU - Segovia, José C.
AU - Díaz De Heredia, Cristina
AU - Sevilla, Julián
AU - Bueren, Juan A.
PY - 2017/9/28
Y1 - 2017/9/28
N2 - © 2017 by The American Society of Hematology Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34+ cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vitro cultured hematopoietic progenitor cells. Transplantation of transduced FA CD34+ cells into immunodeficient mice resulted in reproducible engraftment of myeloid, lymphoid, and CD34+ cells. Importantly, a marked increase in the proportion of phenotypically corrected, patient-derived hematopoietic cells was observed after transplantation with respect to the infused CD34+ graft, indicating the proliferative advantage of corrected FA-A hematopoietic repopulating cells. Our data demonstrate for the first time that optimized protocols of hematopoietic stem cell collection from FA patients, followed by the short and clinically validated transduction of these cells with a therapeutic lentiviral vector, results in the generation of phenotypically corrected HSPCs capable of repopulating and developing proliferation advantage in immunodeficient mice. Our results suggest that clinical approaches for FA gene therapy similar to those used in this study will facilitate hematopoietic repopulation in FA patients with gene corrected HSPCs, opening new prospects for gene therapy of FA patients.
AB - © 2017 by The American Society of Hematology Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34+ cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vitro cultured hematopoietic progenitor cells. Transplantation of transduced FA CD34+ cells into immunodeficient mice resulted in reproducible engraftment of myeloid, lymphoid, and CD34+ cells. Importantly, a marked increase in the proportion of phenotypically corrected, patient-derived hematopoietic cells was observed after transplantation with respect to the infused CD34+ graft, indicating the proliferative advantage of corrected FA-A hematopoietic repopulating cells. Our data demonstrate for the first time that optimized protocols of hematopoietic stem cell collection from FA patients, followed by the short and clinically validated transduction of these cells with a therapeutic lentiviral vector, results in the generation of phenotypically corrected HSPCs capable of repopulating and developing proliferation advantage in immunodeficient mice. Our results suggest that clinical approaches for FA gene therapy similar to those used in this study will facilitate hematopoietic repopulation in FA patients with gene corrected HSPCs, opening new prospects for gene therapy of FA patients.
U2 - https://doi.org/10.1182/blood-2017-03-774174
DO - https://doi.org/10.1182/blood-2017-03-774174
M3 - Article
VL - 130
SP - 1535
EP - 1542
JO - Blood
JF - Blood
SN - 0006-4971
ER -