Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo.
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 1 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.
National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
Kerstin
K
Schwarzwaelder
Steven J
SJ
Howe
Manfred
M
Schmidt
Martijn H
MH
Brugman
Annette
A
Deichmann
Hanno
H
Glimm
Sonja
S
Schmidt
Claudia
C
Prinz
Manuela
M
Wissler
Douglas J S
DJ
King
Fang
F
Zhang
Kathryn L
KL
Parsley
Kimberly C
KC
Gilmour
Joanna
J
Sinclair
Jinhua
J
Bayford
Rachel
R
Peraj
Karin
K
Pike-Overzet
Frank J T
FJ
Staal
Dick
D
de Ridder
Christine
C
Kinnon
Ulrich
U
Abel
Gerard
G
Wagemaker
H Bobby
HB
Gaspar
Adrian J
AJ
Thrasher
Christof
C
von Kalle
D000328:Adult; D017252:CD3 Complex; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D017988:Gammaretrovirus; D005822:Genetic Vectors; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007223:Infant; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D016662:Virus Integration; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*
D017252:CD3 Complex