Stable long-term gene correction with low-dose radiation conditioning in murine X-linked chronic granulomatous disease.
We previously demonstrated that low-dose radiation conditioning impairs murine hematopoietic stem cell function, permitting engraftment of syngeneic fresh and transduced marrow cells. In this study, we directly examined the ability of low-dose radiation conditioning to permit engraftment of transduced long-term repopulating cells in murine X-linked chronic granulomatous disease (X-CGD), which closely mimics the human disease. X-CGD mice conditioned with 160 cGy were transplanted with 20 x 10(6) MSCV-m91Neo-transduced syngeneic X-CGD marrow cells. The presence of oxidase-positive neutrophils in two independent cohorts of transplanted 160-cGy-conditioned X-CGD recipients was determined by nitroblue tetrazolium testing. Transplanted X-CGD mice (n = 9 total) displayed 1-17% oxidase-positive neutrophils 6-16 months post-transplant. Retroviral marking and NADPH-oxidase-positive neutrophils persisted through serial transplantation, verifying that stem cells were transduced. These results establish that low-dose radiation conditioning results in durable engraftment of low but potentially clinically relevant numbers of functionally reconstituted blood cells in a murine model of X-CGD.
Goebel
W Scott
WS
Herman B. Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Pech
Nancy K
NK
Dinauer
Mary C
MC
D000818:Animals; D015316:Genetic Therapy / Q000379:methods; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D019172:Transplantation Conditioning / Q000379:methods; D014916:Whole-Body Irradiation
D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases