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

被引:154
作者
Schwarzwaelder, Kerstin
Howe, Steven J.
Schmidt, Manfred
Brugman, Martijn H.
Deichmann, Annette
Glimm, Hanno
Schmidt, Sonja
Prinz, Claudia
Wissler, Manuela
King, Douglas J. S.
Zhang, Fang
Parsley, Kathryn L.
Gilmour, Kimberly C.
Sinclair, Joanna
Bayford, Jinhua
Peraj, Rachel
Pike-Overzet, Karin
Staal, Frank J. T.
de Ridder, Dick
Kinnon, Christine
Abel, Ulrich
Wagemaker, Gerard
Gaspar, H. Bobby
Thrasher, Adrian J.
von Kalle, Christof
机构
[1] Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany
[2] Univ Freiburg, Fac Biol, Freiburg, Germany
[3] UCL, Inst Child Hlth, Mol Immunol Unit, London, England
[4] Univ Freiburg, Dept Internal Med 1, Freiburg, Germany
[5] Erasmus MC, Dept Hematol, Rotterdam, Netherlands
[6] Great Ormond St Hosp Sick Children, Dept Clin Immunol, London WC1N 3JH, England
[7] Erasmus MC, Dept Immunol, Rotterdam, Netherlands
[8] Delft Univ Technol, Fac Elect Engn Math & Comp Sci, Informat & Commun Theory Grp, Delft, Netherlands
[9] Tumor Ctr Heidelberg Mannheim, Dept Med Biostat, Heidelberg, Germany
[10] Cincinnati Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH USA
基金
英国惠康基金;
关键词
D O I
10.1172/JCI31661
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:2241 / 2249
页数:9
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