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Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.
Hum Gene Ther. 2014 Oct; 25(10):905-14.HG

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+Show Affiliations

1 Department of Neurology, Erasmus University Medical Center , 3000 CA Rotterdam, The Netherlands .No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25222508

Citation

Huston, Marshall W., et al. "Pretransplant Mobilization With Granulocyte Colony-stimulating Factor Improves B-cell Reconstitution By Lentiviral Vector Gene Therapy in SCID-X1 Mice." Human Gene Therapy, vol. 25, no. 10, 2014, pp. 905-14.
Huston MW, Riegman AR, Yadak R, et al. Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice. Hum Gene Ther. 2014;25(10):905-14.
Huston, M. W., Riegman, A. R., Yadak, R., van Helsdingen, Y., de Boer, H., van Til, N. P., & Wagemaker, G. (2014). Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice. Human Gene Therapy, 25(10), 905-14. https://doi.org/10.1089/hum.2014.101
Huston MW, et al. Pretransplant Mobilization With Granulocyte Colony-stimulating Factor Improves B-cell Reconstitution By Lentiviral Vector Gene Therapy in SCID-X1 Mice. Hum Gene Ther. 2014;25(10):905-14. PubMed PMID: 25222508.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice. AU - Huston,Marshall W, AU - Riegman,Adriaan R A, AU - Yadak,Rana, AU - van Helsdingen,Yvette, AU - de Boer,Helen, AU - van Til,Niek P, AU - Wagemaker,Gerard, PY - 2014/9/16/entrez PY - 2014/9/16/pubmed PY - 2015/6/17/medline SP - 905 EP - 14 JF - Human gene therapy JO - Hum. Gene Ther. VL - 25 IS - 10 N2 - 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. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/25222508/Pretransplant_mobilization_with_granulocyte_colony_stimulating_factor_improves_B_cell_reconstitution_by_lentiviral_vector_gene_therapy_in_SCID_X1_mice_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2014.101?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -