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CD34+ peripheral blood progenitors as a target for genetic correction of
the two flavocytochrome b558 defective forms of chronic granulomatous
disease
F Li, GF Linton, S Sekhsaria, N Whiting-Theobald, JP Katkin, JI Gallin and HL Malech
Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892.
Chronic granulomatous disease (CGD) can result from any of four single gene
defects involving components of the superoxide (O2-.)-generating phagocyte
NADPH oxidase (phox). The phox transmembrane flavocytochrome b558 is
composed of two peptides, gp91phox and p22phox. Mutations of gp91phox cause
X-linked CGD, whereas mutations of p22phox cause one of the three autosomal
recessive forms of CGD. We used the Maloney leukemia virus-based MFG
retrovirus vector to produce replication defective retroviruses encoding
gp91phox or p22phox. To maximize viral titer MFG retroviruses do not
contain internal promoter or resistance elements. Epstein-Barr virus
transformed B-lymphocyte cell lines (EBV- B) derived from normal
individuals contain phox components and produce O2-., whereas those derived
from CGD patients show the CGD defect. Transduction of gp91phox or
p22phox-deficient CGD EBV-B lines resulted in correction of O2-. production
from a barely detectable baseline to an average 7.2% and 13.8% of normal
control, respectively, without any selective regimen to enrich for
transduced cells. CD34+ hematopoietic progenitor cells, the therapeutic
target for gene therapy of CGD, were isolated from peripheral blood of CGD
patients, transduced with MFG- phox retroviruses, and differentiated in
culture to mature phagocytes. Transduction of progenitors corrected the
gp91phox (seven patients) and p22phox (two patients) CGD phagocyte oxidase
defect to 2.5% and 4.9% of normal O2-. production, respectively,
representing an 87-fold and 161- fold increase. These studies show
correction of flavocytochrome b558- deficient CGD in primary hematopoietic
progenitors, providing a basis for development of gene therapy for the
X-linked gp91phox and autosomal p22phox-deficient forms of CGD.
Volume 84,
Issue 1,
pp. 53-58,
07/01/1994
Copyright © 1994 by The American Society of Hematology
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