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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 914-922
Long-Term Correction of Phagocyte NADPH Oxidase Activity by
Retroviral-Mediated Gene Transfer in Murine X-Linked Chronic
Granulomatous Disease
Mary C. Dinauer,
Ling Lin Li,
Helga Björgvinsdóttir,
Chunjin Ding, and
Nancy Pech
From Herman B Wells Center for Pediatric Research, Departments of
Pediatrics (Hematology/Oncology) and Medical and Molecular Genetics,
James Whitcomb Riley Hospital for Children, Indiana University School
of Medicine, Indianapolis, IN; and Lund University, Section of
Molecular Medicine and Gene Therapy, Lund, Sweden.
Chronic granulomatous disease (CGD) is an inherited deficiency of
the superoxide-generating phagocyte nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase, resulting in recurrent, severe
bacterial and fungal infections. The X-linked form of this disorder
(X-CGD) results from mutations in the X-linked gene for gp91phox, the larger subunit of the oxidase
flavocytochrome b558. In this study, we used a
murine model of X-CGD to examine the long-term function of retroviral
vectors for expression of gp91phox based on the
murine stem cell virus (MSCV) backbone. NADPH oxidase activity was
reconstituted in neutrophils and macrophages for up to 18 to 24 months
posttransplantation of transduced X-CGD bone marrow into lethally
irradiated syngeneic X-CGD mice. Southern blot analysis and
secondary transplant data showed proviral integration in multilineage
repopulating cells. Although relatively small amounts of recombinant
gp91phox (approximately 5% to 10% of wild-type
levels) were detected in neutrophils after retroviral-mediated gene
transfer, superoxide-generating activity was approximately 20% to 25%
of wild-type mouse neutrophils. Expression of
gp91phox is normally restricted to mature
phagocytes. No obvious toxicity was observed in other hematopoietic
lineages in transplant recipients, and provirus-marked cells were
capable of reconstituting secondary transplant recipients, who also
exhibited NADPH oxidase-positive neutrophils. MSCV-based vectors for
long-term expression of gp91phox may be useful for
gene therapy of human CGD targeted at hematopoietic stem cells.
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