title: Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.
abstract: 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.
authors.affiliation: 1 Department of Neurology, Erasmus University Medical Center , 3000 CA Rotterdam, The Netherlands .
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Huston
authors.forename: Adriaan R A
authors.initials: AR
authors.lastname: Riegman
authors.forename: Rana
authors.initials: R
authors.lastname: Yadak
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Helsdingen
authors.forename: Helen
authors.initials: H
authors.lastname: de Boer
authors.forename: Niek P
authors.initials: NP
authors.lastname: van Til
authors.forename: Gerard
authors.initials: G
authors.lastname: Wagemaker
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000276:immunology* / Q000628:therapy
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D016179:Granulocyte Colony-Stimulating Factor