| First Author | Chatziandreou I | Year | 2011 |
| Journal | Exp Hematol | Volume | 39 |
| Issue | 6 | Pages | 643-52 |
| PubMed ID | 21426924 | Mgi Jnum | J:186953 |
| Mgi Id | MGI:5433816 | Doi | 10.1016/j.exphem.2011.03.003 |
| Citation | Chatziandreou I, et al. (2011) Genetic correction of X-linked chronic granulomatous disease with novel foamy virus vectors. Exp Hematol 39(6):643-52 |
| abstractText | OBJECTIVE: The X-linked form of chronic granulomatous disease (X-CGD) results from mutations in the CYBB gene encoding gp91(phox), the larger subunit of the oxidase flavocytochrome b(558). Affected individuals suffer from recurrent life-threatening infections due to impaired superoxide production by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. Novel foamy virus vectors expressing the human codon-optimized gp91(phox) were evaluated for the genetic correction of the disease in the X-CGD cell line and in X-CGD mouse model. MATERIALS AND METHODS: The vectors were evaluated in vitro, in the human X-CGD PLB-985 cell line and in the X-CGD bone marrow Lin(-) cells. Transplantation of transduced Lin(-) cells was performed in X-CGD mice after busulfan conditioning. Real-time polymerase chain reaction was used for chimerism and vector copy number determination. Restoration of reduced NADPH oxidase production was assessed by nitrobluetetrazolium and dihydrorhodamine assays. RESULTS: High and stable gp91(phox) expression, as well as reconstitution of reduced NADPH activity, was achieved in the human X-CGD PLB-985 cell line and in primary murine X-CGD hematopoietic stem cells ex vivo. Transplantation of transduced bone marrow hematopoietic stem cells in the murine model of X-CGD, even with low multiplicities of infection (MOI), reconstituted the levels of oxidase-producing neutrophils and provided enzymatic activity that reached 70% of normal. CONCLUSIONS: Foamy virus vectors expressing the human gp91(phox) transgene constitute potential candidates for the gene therapy of CGD because they combine lack of pathogenicity with efficacy even at low MOI. |
