We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene.
- Authors
Hara, T.; Kume, A.; Hanazono, Y.; Mizukami, H.; Okada, T.; Tsurumi, H.; Moriwaki, H.; Ueda, Y.; Hasegawa, M.; Ozawa, K.
- Abstract
Hematopoietic stem cell gene therapy has not provided clinical success in disorders such as chronic granulomatous disease (CGD), where genetically corrected cells do not show a selective advantage in vivo. To facilitate selective expansion of transduced cells, we have developed a fusion receptor system that confers drug-induced proliferation. Here, a‘selective amplifier gene (SAG)’encodes a chimeric receptor (GcRER) that generates a mitotic signal in response to estrogen. We evaluated the in vivo efficacy of SAG-mediated cell expansion in a mouse disease model of X-linked CGD (X-CGD) that is deficient in the NADPH oxidase gp91phox subunit. Bone marrow cells from X-CGD mice were transduced with a bicistronic retrovirus encoding GcRER and gp91phox, and transplanted to lethally irradiated X-CGD recipients. Estrogen was administered to a cohort of the transplants, and neutrophil superoxide production was monitored. A significant increase in oxidase-positive cells was observed in the estrogen-treated mice, and repeated estrogen administration maintained the elevation of transduced cells for 20 weeks. In addition, oxidase-positive neutrophils were increased in the X-CGD transplants given the first estrogen even at 9 months post-transplantation. These results showed that the SAG system would enhance the therapeutic effects by boosting genetically modified, functionally corrected cells in vivo.Gene Therapy (2004) 11, 1370-1377. doi:10.1038/sj.gt.3302317; Published online 1 July 2004
- Subjects
NEUTROPHILS; GENE therapy; ESTROGEN replacement therapy; CHRONIC granulomatous disease treatment; GENETIC transformation; CELL proliferation
- Publication
Gene Therapy, 2004, Vol 11, Issue 18, p1370
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3302317