Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene

Gene Therapy
T HaraKeiya Ozawa

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-tra...Continue Reading

References

Feb 21, 1991·The New England Journal of Medicine·UNKNOWN International Chronic Granulomatous Disease Cooperative Study Group
Sep 1, 1995·The Journal of Experimental Medicine·S H JacksonS M Holland
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·W S PearD Baltimore
Jan 13, 1995·Journal of Immunological Methods·S J VowellsT A Fleisher
Nov 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·L ZhenM C Dinauer
Aug 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·S SekhsariaH L Malech
Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·H L MalechJ I Gallin
Mar 1, 2000·The Journal of Laboratory and Clinical Medicine·A Kume, M C Dinauer
Apr 28, 2000·Science·M Cavazzana-CalvoA Fischer
Sep 6, 2000·Nature Genetics·L JinC A Blau
Apr 21, 2001·Blood·T Neff, C A Blau
Apr 19, 2002·The New England Journal of Medicine·Salima Hacein-Bey-AbinaMarina Cavazzana-Calvo
May 10, 2002·International Journal of Hematology·David W EmeryGeorge Stamatoyannopoulos
Jul 20, 2002·Bone Marrow Transplantation·A KumeK Ozawa
Aug 30, 2002·Blood·Tobias NeffC Anthony Blau
Dec 5, 2002·International Journal of Hematology·Akihiro KumeKeiya Ozawa
Jan 17, 2003·The New England Journal of Medicine·Salima Hacein-Bey-AbinaAlain Fischer
Apr 1, 2003·The Journal of Gene Medicine·Akihiro KumeKeiya Ozawa
Jul 2, 2003·Nature Reviews. Cancer·Donald B KohnJoseph C Glorioso

❮ Previous
Next ❯

Citations

Mar 3, 2007·Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology·Hiroyuki Nunoi
Nov 22, 2005·Oncogene·J Michael MathisDavid T Curiel

❮ Previous
Next ❯

Related Concepts

Related Feeds

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.