Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients.
Blood
; 130(13): 1535-1542, 2017 09 28.
Article
em En
| MEDLINE
| ID: mdl-28801449
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução Genética
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Terapia Genética
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Transplante de Células-Tronco Hematopoéticas
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Proteína do Grupo de Complementação C da Anemia de Fanconi
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Anemia de Fanconi
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Vetores Genéticos
Tipo de estudo:
Guideline
Limite:
Animals
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Child
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Child, preschool
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Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Espanha