Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.
Little is known about the potential for engraftment of autologous hematopoietic stem cells in human adults not subjected to myeloablative conditioning regimens. Five adult patients with the p47(phox) deficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34(+) peripheral blood stem cells (PBSCs) that had been transduced ex vivo with a recombinant retrovirus encoding normal p47(phox). Although marrow conditioning was not given, functionally corrected granulocytes were detectable in peripheral blood of all five patients. Peak correction occurred 3-6 weeks after infusion and ranged from 0.004 to 0.05% of total peripheral blood granulocytes. Corrected cells were detectable for as long as 6 months after infusion in some individuals. Thus, prolonged engraftment of autologous PBSCs and continued expression of the transduced gene can occur in adults without conditioning. This trial also piloted the use of animal protein-free medium and a blood-bank-compatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs. These features enhance the safety of PBSCs directed gene therapy.
Malech
H L
HL
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, MSC 1886, Bethesda, MD 20892, USA. hmalech@nih.gov
Maples
P B
PB
Whiting-Theobald
N
N
Linton
G F
GF
Sekhsaria
S
S
Vowells
S J
SJ
Li
F
F
Miller
J A
JA
DeCarlo
E
E
Holland
S M
SM
Leitman
S F
SF
Carter
C S
CS
Butz
R E
RE
Read
E J
EJ
Fleisher
T A
TA
Schneiderman
R D
RD
Van Epps
D E
DE
Spratt
S K
SK
Maack
C A
CA
Rokovich
J A
JA
Cohen
L K
LK
Gallin
J I
JI
D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34; D001781:Blood Component Removal; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D006098:Granulocytes / Q000201:enzymology*; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D019255:NADPH Oxidases / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
D018952:Antigens, CD34; D010750:Phosphoproteins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1