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Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo

Schwarzwaelder, K; Howe, SJ; Schmidt, M; Brugman, MH; Deichmann, A; Glimm, H; Schmidt, S; ... von Kalle, C; + view all (2007) Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J CLIN INVEST , 117 (8) 2241 - 2249. 10.1172/JCI31661. Green open access

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Abstract

We treated 10 children with X-linked SCID (SCID-X1) using gammaretrovirus-mediated gene transfer. Those with sufficient follow-up were found to have recovered substantial immunity in the absence of any serious adverse events up to 5 years after treatment. To determine the influence of vector integration on lymphoid reconstitution, we compared retroviral integration sites (RISs) from peripheral blood CD3(+) T lymphocytes of 5 patients taken between 9 and 30 months after transplantation with transduced CD34(+) progenitor cells derived from 1 further patient and I healthy donor. Integration occurred preferentially in gene regions on either side of transcription start sites, was clustered, and correlated with the expression level in CD34(+) progenitors during transduction. In contrast to those in CD34(+) cells, RISs recovered from engrafted CD3(+)T cells were significantly overrepresented within or near genes encoding proteins with kinase or transferase activity or involved in phosphorus metabolism. Although gross patterns of gene expression were unchanged in transduced cells, the divergence of RIS target frequency between transduced progenitor cells and post-thymic T lymphocytes indicates that vector integration influences cell survival, engraftment, or proliferation.

Type: Article
Title: Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI31661
Keywords: SEVERE COMBINED IMMUNODEFICIENCY, RETROVIRAL GENE MARKING, HUMAN GENOME, THERAPY, CELLS, LONG, ADA, RECONSTITUTION, TRANSCRIPTION, EXPRESSION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/7490
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