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Genetic correction of p67phox deficient chronic granulomatous disease using
peripheral blood progenitor cells as a target for retrovirus mediated gene
transfer
WM Weil, GF Linton, N Whiting-Theobald, SJ Vowells, SP Rafferty, F Li and HL Malech
Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892- 1886, USA.
Chronic granulomatous disease (CGD) can result from any of four single gene
defects involving the components of the superoxide (O-2) generating
phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We
show that transduction of peripheral blood CD34+ hematopoietic progenitors
from a p67phox deficient CGD patient with replication defective amphotropic
retrovirus encoding p67phox (MFGS- p67phox) significantly corrected the CGD
functional defect in phagocyte oxidase activity in vitro. Using a
chemiluminescence assay of oxidase activity, we showed that transduced
patient CD34+ progenitors differentiating to myeloid cells in culture
produced 25% of the total superoxide produced by normal CD34+ progenitors
differentiating in culture. A flow cytometric assay of oxidase activity
used to assess the oxidase function of individual cells in the cultures
indicated that up to 32% of maturing granulocytes derived from transduced
CD34+ progenitors from the p67phox CGD patient were oxidase positive with
the average level of correction per granulocyte of 85% of that seen with
granulocytes in similar cultures of CD34+ progenitors from normal
volunteers. Nitroblue tetrazolium dye reduction assays of colonies of
transduced progenitors in soft agar indicated that in some studies
restoration of oxidase activity occurred in myeloid cells within 44% of
granulocyte-erythrocyte-monocyte colonies, and within 28% of the combined
group of granulocyte colonies/monocyte colonies/granulocyte monocyte
colonies. These high correction rates were achieved without any selective
regimen to enrich for transduced cells. This study provides a basis for
development of gene therapy for the p67phox deficient form of CGD.
Volume 89,
Issue 5,
pp. 1754-1761,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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