Stable long-term gene correction with low-dose radiation conditioning in murine X-linked chronic granulomatous disease

• Published in: Blood cells, molecules, & diseases Vol. 33; no. 3; pp. 365 - 371
• Main Authors: Goebel, W. Scott, Pech, Nancy K., Dinauer, Mary C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2004
• Subjects: Animals; Chronic granulomatous disease; Gene therapy; Genetic Therapy - methods; Granulomatous Disease, Chronic - genetics; Granulomatous Disease, Chronic - metabolism; Granulomatous Disease, Chronic - therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - enzymology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Knockout; Murine models; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Stem cell transplantation; Submyeloablative conditioning; Transplantation Conditioning - methods; Whole-Body Irradiation; Stem cell transplantation; Chronic granulomatous disease; Gene therapy; Submyeloablative conditioning; Murine models
• ISSN: 1079-9796; 1096-0961
• DOI: 10.1016/j.bcmd.2004.06.007

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.