Plerixafor+G-CSF–mobilized CD34+ cells represent an optimal graft source for thalassemia gene therapy
| Autor: | Carsten W. Lederer, Nikolaos Zogas, Michel Sadelain, Marina Kleanthous, Nikoletta Psatha, Garyfalia Karponi, Constantinos Tsatalas, George Stamatoyannopoulos, Jennifer E. Adair, Evangelia Yannaki, Achilles Anagnostopoulos, Isabelle Riviere, Fani Zervou |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Benzylamines
Genetic enhancement medicine.medical_treatment Immunology Genetic Vectors CD34 Gene Dosage Gene Expression Antigens CD34 Hematopoietic stem cell transplantation beta-Globins Biology Cyclams Biochemistry Transplantation Autologous 03 medical and health sciences Mice 0302 clinical medicine Heterocyclic Compounds Granulocyte Colony-Stimulating Factor medicine Animals Humans 030304 developmental biology Mice Knockout 0303 health sciences Plerixafor beta-Thalassemia Hematopoietic Stem Cell Transplantation Cell Biology Hematology Gene Therapy Genetic Therapy Hematopoietic Stem Cells Hematopoietic Stem Cell Mobilization Granulocyte colony-stimulating factor Transplantation Haematopoiesis 030220 oncology & carcinogenesis Cancer research Heterografts Stem cell medicine.drug |
| Zdroj: | Blood |
| Popis: | Globin gene therapy requires abundant numbers of highly engraftable, autologous hematopoietic stem cells expressing curative levels of β-globin on differentiation. In this study, CD34+ cells from 31 thalassemic patients mobilized with hydroxyurea+granulocyte colony-stimulating factor (G-CSF), G-CSF, Plerixafor, or Plerixafor+G-CSF were transduced with the TNS9.3.55 β-globin lentivector and compared for transducibility and globin expression in vitro, as well as engraftment potential in a xenogeneic model after partial myeloablation. Transduction efficiency and vector copy number (VCN) averaged 48.4 ± 2.8% and 1.91 ± 0.04, respectively, whereas expression approximated the one-copy normal β-globin output. Plerixafor+G-CSF cells produced the highest β-globin expression/VCN. Long-term multilineage engraftment and persistent VCN and vector expression was encountered in all xenografted groups, with Plerixafor+G-CSF-mobilized cells achieving superior short-term engraftment rates, with similar numbers of CD34+ cells transplanted. Overall, Plerixafor+G-CSF not only allows high CD34+ cell yields but also provides increased β-globin expression/VCN and enhanced early human chimerism under nonmyeloablative conditions, thus representing an optimal graft for thalassemia gene therapy. |
| Databáze: | OpenAIRE |
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