Title

Retroviral Vector Integration In Post-Transplant Hematopoiesis In Mice Conditioned With Either Submyeloablative Or Ablative Irradiation

Keywords

Chronic granulomatous disease; Insertional mutagenesis; NADPH oxidase; Retrovirus

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 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 γ-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. © 2009 Macmillan Publishers Limited All rights reserved.

Publication Date

12-3-2009

Publication Title

Gene Therapy

Volume

16

Issue

12

Number of Pages

1452-1464

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1038/gt.2009.96

Socpus ID

73849103940 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/73849103940

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