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- Title
Retroviral vector integration in post-transplant hematopoiesis in mice conditioned with either submyeloablative or ablative irradiation.
- Authors
Sadat, M. A.; Dirscherl, S.; Sastry, L.; Dantzer, J.; Pech, N.; Griffin, S.; Hawkins, T.; Zhao, Y.; Barese, C. N.; Cross, S.; Orazi, A.; An, C.; Goebel, W. S.; Yoder, M. C.; Li, X.; Grez, M.; Cornetta, K.; Mooney, S. D.; Dinauer, M. C.
- Abstract
X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH-oxidase activity caused by defects in the gene-encoding gp91phox. Here, we evaluated strategies for less intensive conditioning for gene therapy of genetic blood disorders without selective advantage for gene correction, such as might be used in a human X-CGD protocol. We compared submyeloablative with ablative irradiation as conditioning in murine X-CGD, examining engraftment, oxidase activity and vector integration in mice transplanted with marrow transduced with a γ-retroviral vector for gp91phox expression. The frequency of oxidase-positive neutrophils in the donor population was unexpectedly higher in many 300 cGy-conditioned mice compared with lethally irradiated recipients, as was the fraction of vector-marked donor secondary CFU-S12. Vector integration sites in marrow, spleen and secondary CFU-S12 DNA from primary recipients were enriched for cancer-associated genes, including Evi1, and integrations in or near cancer-associated genes were more frequent in marrow and secondary CFU-S12 from 300 cGy-conditioned mice compared with fully ablated mice. These findings support the concept that vector integration can confer a selection bias, and suggest that the intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis.
- Subjects
CHRONIC granulomatous disease; IMMUNODEFICIENCY; GENE therapy; RETROVIRUS diseases; HEMATOPOIESIS
- Publication
Gene Therapy, 2009, Vol 16, Issue 12, p1452
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2009.96