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Blood, 1 July 2002, Vol. 100, No. 1, pp. 72-79
GENE THERAPY
Retroviral transduction of IL2RG into
CD34+ cells from X-linked severe combined immunodeficiency
patients permits human T- and B-cell development in sheep
chimeras
Emily J. Tsai,
Harry L. Malech,
Martha R. Kirby,
Amy P. Hsu,
Nancy E. Seidel,
Christopher D. Porada,
Esmail D. Zanjani,
David M. Bodine, and
Jennifer M. Puck
From the National Human Genome Research Institute, the
Howard Hughes Medical Institute/National Institutes of Health Research
Scholar Program, and the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD; and the
Department of Medicine, University of Nevada School of Medicine, Reno.
X-linked severe combined immunodeficiency (XSCID) is caused by
mutations of the common gamma chain of cytokine receptors,  c. Because bone marrow transplantation (BMT) for XSCID
does not provide complete immune reconstitution for many patients and
because of the natural selective advantage conferred on lymphoid
progenitors by the expression of normal c, XSCID is a
good candidate disease for therapeutic retroviral gene transfer to
hematopoietic stem cells. We studied XSCID patients who have persistent
defects in B-cell and/or combined B- and T-cell function despite having
received T cell-depleted haploidentical BMT. We compared transduction
of autologous B-cell lines and granulocyte colony-stimulating
factor-mobilized peripheral CD34+ cells from these
patients using an MFGS retrovirus vector containing the
c gene IL2RG pseudotyped with amphotropic,
gibbon ape leukemia virus, or RD114 envelopes. Transduced
B-cell lines and peripheral CD34+ cells demonstrated
provirus integration and new cell-surface c expression.
The chimeric sheep model was exploited to test development of XSCID
CD34+ cells into mature myeloid and lymphoid lineages.
Transduced and untransduced XSCID CD34+ cells injected
into developing sheep fetuses gave rise to myeloid cells.
However, only transduced  progenitors from XSCID
patients developed into T and B cells. These results suggest that gene
transfer to autologous peripheral CD34+ cells using
MFGS-gc retrovirus may benefit XSCID patients with persistent
T- and B-cell deficits despite prior BMT.
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