Retroviral Gene Therapy for X-linked Chronic Granulomatous Disease: Results From Phase I/II Trial

X-linked chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by a defect in the gp91phox 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 transduce...

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Bibliographic Details
Published in:Molecular therapy 2011-11, Vol.19 (11), p.2092-2101
Main Authors: Kang, Hyoung Jin, Bartholomae, Cynthia C, Paruzynski, Anna, Arens, Anne, Kim, Sujeong, Yu, Seung Shin, Hong, Youngtae, Joo, Chang-Wan, Yoon, Nam-Kyung, Rhim, Jung-Woo, Kim, Joong Gon, Von Kalle, Christof, Schmidt, Manfred, Kim, Sunyoung, Ahn, Hyo Seop
Format: Article
Language:English
Subjects:
Adolescent
Child
Clinical trials
Disease
Efficiency
Gastroenteritis
Gene Expression Profiling
Gene therapy
Genetic Therapy
Genetic Vectors - adverse effects
Granulocytes
Granulomatous Disease, Chronic - therapy
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cells - metabolism
Humans
Infections
Male
Medical research
Membrane Glycoproteins - genetics
NADPH Oxidase 2
NADPH Oxidases - genetics
Original
Patients
Pediatrics
Pneumonia
Retroviridae - genetics
Stem cells
Transduction, Genetic
Treatment Outcome
University colleges
Virus Integration
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Summary:X-linked chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by a defect in the gp91phox 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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2011.166