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 p47phoxdeficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34+peri...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-10, Vol.94 (22), p.12133-12138
Main Authors: Malech, H L, Maples, P B, Whiting-Theobald, N, Linton, G F, Sekhsaria, S, Vowells, S J, Li, F, Miller, J A, DeCarlo, E, Holland, S M, Leitman, S F, Carter, C S, Butz, R E, Read, E J, Fleisher, T A, Schneiderman, R D, Van Epps, D E, Spratt, S K, Maack, C A, Rokovich, J A, Cohen, L K, Gallin, J I
Format: Article
Language:English
Subjects:
Adolescent
Adult
Antigens, CD34
Biological Sciences
Blood
Blood cells
Blood Component Removal
Bone marrow
Cells
Cultured cells
Disease
Female
Flow Cytometry
Follow-Up Studies
Gene therapy
Genetic Therapy - methods
Granulocytes
Granulocytes - enzymology
Granulomatous Disease, Chronic - therapy
Hematopoietic Stem Cell Transplantation
Humans
Male
NADPH Oxidases - biosynthesis
Neutrophils
Oxidases
Phosphoproteins - deficiency
Phosphoproteins - genetics
Phosphoproteins - immunology
Retroviridae - genetics
Stem cells
Transduction, Genetic
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Summary: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 p47phoxdeficiency 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 p47phox. 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.22.12133