Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice.
Gene therapy by use of integrating vectors carrying therapeutic transgene sequences offers the potential for a permanent cure of genetic diseases by stable vector insertion into the patients' chromosomes. However, three cases of T cell lymphoproliferative disease have been identified almost 3 years after retrovirus gene therapy for X-linked severe combined immune deficiency. In two of these cases vector insertion into the LMO2 locus was implicated in leukemogenesis, demonstrating that a more profound understanding is required of the genetic and molecular effects imposed on the host by vector integration or transgene expression. In vivo models to test for retro- and lentiviral vector safety prior to clinical application are therefore needed. Here we present a high incidence of lentiviral vector-associated tumorigenesis following in utero and neonatal gene transfer in mice. This system may provide a highly sensitive model to investigate integrating vector safety prior to clinical application.
Themis
Mike
M
Gene Therapy Research Group, Section of Cell and Molecular Biology, Imperial College London, UK. m.themis@imperial.ac.uk
Waddington
Simon N
SN
Schmidt
Manfred
M
von Kalle
Christof
C
Wang
Yoahe
Y
Al-Allaf
Faisal
F
Gregory
Lisa G
LG
Nivsarkar
Megha
M
Themis
Matthew
M
Holder
Maxine V
MV
Buckley
Suzanne M K
SM
Dighe
Niraja
N
Ruthe
Alaine T
AT
Mistry
Ajay
A
Bigger
Brian
B
Rahim
Ahad
A
Nguyen
Tuan H
TH
Trono
Didier
D
Thrasher
Adrian J
AJ
Coutelle
Charles
C
D000818:Animals; D000831:Animals, Newborn; D005333:Fetus; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic