Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

Autor: Adriaan R.A. Riegman, Rana Yadak, Marshall W. Huston, Helen de Boer, Niek P. van Til, Yvette van Helsdingen, Gerard Wagemaker
Přispěvatelé: İç Hastalıkları, Neurology, Clinical Genetics, Hematology
Rok vydání: 2014
Předmět:
Male
Transplantation Conditioning
Genetic enhancement
medicine.medical_treatment
T-Lymphocytes
Genetic Vectors
Hematopoietic stem cell transplantation
Research & Experimental Medicine
X-Linked Combined Immunodeficiency Diseases
Lymphocyte Depletion
Bone Marrow Stem Cell Transplantation
Mice
Transduction
Genetic
Granulocyte Colony-Stimulating Factor
Genetics
medicine
Animals
Molecular Biology
Hematopoietic Stem Cell Mobilization
Research Articles
Genetics & Heredity
Mice
Knockout
Severe combined immunodeficiency
B-Lymphocytes
business.industry
Lentivirus
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell
Genetic Therapy
medicine.disease
Hematopoietic Stem Cells
Granulocyte colony-stimulating factor
Disease Models
Animal
medicine.anatomical_structure
Biotechnology & Applied Microbiology
Immunology
Molecular Medicine
Female
Bone marrow
business
Interleukin Receptor Common gamma Subunit
Zdroj: Human Gene Therapy, 25(10), 905-914. Mary Ann Liebert Inc.
ISSN: 1043-0342
DOI: 10.1089/hum.2014.101
Popis: Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.
Databáze: OpenAIRE
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