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Enhanced host defense after gene transfer in the murine p47phox- deficient
model of chronic granulomatous disease
M Mardiney , SH Jackson, SK Spratt, F Li, SM Holland and HL Malech
Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892- 1886, USA.
The p47phox-/- mouse exhibits a phenotype similar to that of human chronic
granulomatous disease (CGD) and, thus, is an excellent model for the study
of gene transfer technology. Using the Moloney murine leukemia virus-based
retroviral vector MFG-S encoding the human form of p47phox, we performed ex
vivo gene transfer into Sca-1+ p47phox-/- marrow progenitor cells without
conditioning of donors with 5- fluorouracil. Transduced progenitors were
transplanted into moderately irradiated (500 cGy), G-CSF preconditioned
sibling p47phox-/- mice. Using the fluorescent probe dihydrorhodamine 123
(DHR), in vivo biochemical correction of the superoxide-generating NADPH
oxidase system was detected by flow cytometry in 12.3% +/- 0.9% of phorbol
myristate acetate-stimulated peripheral blood neutrophils at 4 weeks and
2.6% +/- 1.0% at 14 weeks after transplantation. Following gene therapy,
mice were challenged with the CGD pathogen Burkholderia (formerly
Pseudomonas) cepacia and bacteremia levels were assessed at 24 hours and 7
days after inoculation. At both time points, bacteremia levels in gene
corrected p47phox-/- mice were significantly lower than untreated
p47phox-/- mice (0.89 +/- 0.30 colonies v 237.7 +/- 83.6 colonies at 24
hours, P < .02; 4.0 +/- 2.0 colonies v 110.2 +/- 26.5 colonies at 7
days, P < .0014). More importantly, Kaplan-Meier survival analysis
showed a significant survival advantage of gene corrected versus untreated
p47phox-/- mice (P < .001). Thus, stem-cell-directed ex vivo gene
therapy is capable of restoring phagocyte oxidant- dependent host-defense
function in this mouse model of a human immune- system disorder.
Volume 89,
Issue 7,
pp. 2268-2275,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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