title: Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial.
abstract: X-linked chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by a defect in the gp91(phox) gene. In an effort to treat X-CGD, we investigated the safety and efficacy of gene therapy using a retroviral vector, MT-gp91. Two X-CGD patients received autologous CD34(+) cells transduced with MT-gp91 after a conditioning regimen consisting of fludarabine and busulfan. The level of gene-marked cells was highest at day 21 (8.3 and 11.7% in peripheral blood cells) but decreased to 0.08 and 0.5%, respectively, 3 years after gene transfer. The level of functionally corrected cells, as determined by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, reached a peak at day 17 (6.5% patient 1 (P1) and 14.3% patient 2 (P2) of total granulocytes) and declined to 0.05% (P1) and 0.21% (P2), 3 years later. Some retroviral vectors were found to have integrated within or close to the proto-oncogenes MDS1-EVI1, PRDM16, and CCND2; however, no abnormal cell expansion or related hematological malignancy was observed. Overall, the gene transfer procedure did not produce any serious adverse effects and was able to convert a significant fraction of blood cells to biologically functional cells, albeit for a short period of time.
authors: Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
authors: Hyoung Jin
authors: HJ
authors: Kang
authors: Cynthia C
authors: CC
authors: Bartholomae
authors: Anna
authors: A
authors: Paruzynski
authors: Anne
authors: A
authors: Arens
authors: Sujeong
authors: S
authors: Kim
authors: Seung Shin
authors: SS
authors: Yu
authors: Youngtae
authors: Y
authors: Hong
authors: Chang-Wan
authors: CW
authors: Joo
authors: Nam-Kyung
authors: NK
authors: Yoon
authors: Jung-Woo
authors: JW
authors: Rhim
authors: Joong Gon
authors: JG
authors: Kim
authors: Christof
authors: C
authors: Von Kalle
authors: Manfred
authors: M
authors: Schmidt
authors: Sunyoung
authors: S
authors: Kim
authors: Hyo Seop
authors: HS
authors: Ahn
mesh_terms: D000293:Adolescent; D002648:Child; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000009:adverse effects; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D016896:Treatment Outcome; D016662:Virus Integration
chemical_list: D008562:Membrane Glycoproteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases