Gene therapy of chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox gene and a selectable marker gene were constructed. The ability of these vectors to restore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34+ cells obtained from X-CGD patients. Under optimal conditions 80% of the CD34+ cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced cells was 68.9% of normal levels. Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.
Grez
M
M
Laboratory for Molecular Virology, Georg-Speyer-Haus, Frankfurt, Germany.
Becker
S
S
Saulnier
S
S
Knöss
H
H
Ott
M G
MG
Maurer
A
A
Dinauer
M C
MC
Hoelzer
D
D
Seger
R
R
Hossle
J P
JP
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D016897:Respiratory Burst; D012190:Retroviridae / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014161:Transduction, Genetic; D014960:X Chromosome / Q000235:genetics
D018952:Antigens, CD34; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases