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Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal
and neonatal mice.
Themis, M, Waddington, S, Schmidt, M, von Kalle, C, Wang, Y, Al-Allaf, F, Gregory,
L, Nivsarkar, M, Themis, M, Holder, M, Buckley, S, Dighe, N, Ruthe, A, Mistry, A,
Bigger, B, Rahim, A, Nguyen, T, Trono, D, Thrasher, A, Coutelle, C
Molecular Therapy. 2005;12( 4):763-71.
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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.