Adenovirus-mediated gene transfer into monocyte-derived macrophages of patients with X-linked chronic granulomatous disease: ex vivo correction of deficient respiratory burst.
The underlying cause of X-linked chronic granulomatous disease (X-CGD) is mutations in the gp91phox coding gene. Gp91phox is the larger subunit of the cytochrome b558, the membrane-bound terminal redox centre of the respiratory burst oxidase (NADPH oxidase). We have constructed a recombinant adenovirus which contains a functional copy of the human gp91phox cDNA under the control of the cytomegalovirus (CMV) enhancer/promoter region. This vector was used to infect monocyte-derived macrophages of gp91phox-deficient CGD patients. Expression of the gp91phox transgene resulted in ex vivo reconstitution of the respiratory burst activity. Nitroblue-tetrazolium staining indicated that 74% of the patient cells could be phenotypically corrected when compared with a corresponding control culture of normal monocyte-derived macrophages. Adenoviral gene transfer may become a promising tool and gain therapeutical potential by the targeting of autologous monocytes. Genetically corrected autologous monocytes may be used for supportive treatment of X-CGD patients to overcome acute life-threatening infections. Establishment of adenovirus-mediated reconstitution of gp91phox-deficient monocytes therefore represents a first step towards the development of a clinically applicable supportive transient somatic gene therapy in CGD.
Schneider
S D
SD
Division of Immunology/Haematology, University Children's Hospital, Zurich, Switzerland.
Rusconi
S
S
Seger
R A
RA
Hossle
J P
JP
D000256:Adenoviridae; D002478:Cells, Cultured; D015870:Gene Expression; D018014:Gene Transfer Techniques; D008040:Genetic Linkage; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006105:Granulomatous Disease, Chronic / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016897:Respiratory Burst / Q000235:genetics*; D019076:Transgenes; D014960:X Chromosome
D019255:NADPH Oxidases