| Title: |
Retroviral vector integration in post-transplant hematopoiesis in mice conditioned with either submyeloablative or ablative irradiation |
| Authors: |
Sadat, Mohammed A.; Dirscherl, Sara; Sastry, Lakshmi; Dantzer, Jessica; Pech, Nancy; Griffin, Samantha; Hawkins, Troy; Zhao, Yiqiang; Barese, Cecilia N.; Cross, Scott; Orazi, Attilio; An, Caroline; Goebel, W. Scott; Yoder, Mervin C.; Li, Xiaoman; Grez, Manuel; Cornetta, Kenneth; Mooney, Sean D.; Dinauer, Mary C. |
| Contributors: |
Pediatrics, School of Medicine |
| Source: |
PMC |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2009 |
| Collection: |
Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| Subject Terms: |
Chronic granulomatous disease; Hematopoietic stem cell transplantation; Neoplasms; Genetic vectors; Retroviridae; Stem cells |
| Description: |
X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH-oxidase activity caused by defects in the gene-encoding gp91(phox). 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 gamma-retroviral vector for gp91(phox) 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Gene Therapy; https://hdl.handle.net/1805/52712 |
| Availability: |
https://hdl.handle.net/1805/52712 |
| Rights: |
Publisher Policy |
| Accession Number: |
edsbas.1A07EF9A |
| Database: |
BASE |