TY - JOUR
T1 - Stable long-term gene correction with low-dose radiation conditioning in murine X-linked chronic granulomatous disease
AU - Goebel, W. Scott
AU - Pech, Nancy K.
AU - Dinauer, Mary C.
N1 - Funding Information:
This work was supported by the National Heart, Lung and Blood Institute P01 HL53586, and the Riley Memorial Association. The Wells Center for Pediatric Research is a Center for Excellence in Molecular Hematology funded by the National Institute of Diabetes and Digestive and Kidney Diseases (P50 DK 49218). WSG was a William Kennedy Fellow of the National Childhood Cancer Foundation. We thank Drs. Karen Pollok and Mervin C. Yoder for many helpful discussions, and Shari Upchurch and Trish Marsh for assistance with preparing the manuscript.
PY - 2004/11
Y1 - 2004/11
N2 - 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 × 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.
AB - 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 × 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.
KW - Chronic granulomatous disease
KW - Gene therapy
KW - Murine models
KW - Stem cell transplantation
KW - Submyeloablative conditioning
UR - https://www.scopus.com/pages/publications/7544248864
U2 - 10.1016/j.bcmd.2004.06.007
DO - 10.1016/j.bcmd.2004.06.007
M3 - Article
C2 - 15528159
AN - SCOPUS:7544248864
SN - 1079-9796
VL - 33
SP - 365
EP - 371
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
IS - 3
ER -