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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-08-2663.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2199-2205
GENE THERAPY
Retroviral transduction efficiency of G-CSF+SCF-mobilized
peripheral blood CD34+ cells is superior to G-CSF or
G-CSF+Flt3-L-mobilized cells in nonhuman primates
Peiman Hematti,
Stephanie
E. Sellers,
Brian A. Agricola,
Mark E. Metzger,
Robert E. Donahue, and
Cynthia E. Dunbar
From the Hematology Branch, NHLBI, National Institutes
of Health, Bethesda, MD.
Gene transfer experiments in nonhuman primates have been shown to
be predictive of success in human clinical gene therapy trials. In most
nonhuman primate studies, hematopoietic stem cells (HSCs) collected
from the peripheral blood or bone marrow after administration of
granulocyte colony-stimulating factor (G-CSF) + stem cell
factor (SCF) have been used as targets, but this cytokine combination
is not generally available for clinical use, and the optimum target
cell population has not been systematically studied. In our current
study we tested the retroviral transduction efficiency of rhesus
macaque peripheral blood CD34+ cells collected after
administration of different cytokine mobilization regimens, directly
comparing G-CSF+SCF versus G-CSF alone or G-CSF+Flt3-L in competitive
repopulation assays. Vector supernatant was added daily for 96 hours in
the presence of stimulatory cytokines. The transduction efficiency of
HSCs as assessed by in vitro colony-forming assays was equivalent in
all 5 animals tested, but the in vivo levels of mononuclear cell and
granulocyte marking was higher at all time points derived from target
CD34+ cells collected after G-CSF+SCF mobilization compared
with target cells collected after G-CSF (n = 3) or G-CSF+Flt3-L
(n = 2) mobilization. In 3 of the animals long-term marking levels of
5% to 25% were achieved, but originating only from the
G-CSF+SCF-mobilized target cells. Transduction efficiency of HSCs
collected by different mobilization regimens can vary significantly and
is superior with G-CSF+SCF administration. The difference in
transduction efficiency of HSCs collected from different sources should
be considered whenever planning clinical gene therapy trials and should
preferably be tested directly in comparative studies.
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