title: Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice.
abstract: 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.
authors.affiliation: Gene Therapy Research Group, Section of Cell and Molecular Biology, Imperial College London, UK. m.themis@imperial.ac.uk
authors.forename: Mike
authors.initials: M
authors.lastname: Themis
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Yoahe
authors.initials: Y
authors.lastname: Wang
authors.forename: Faisal
authors.initials: F
authors.lastname: Al-Allaf
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Gregory
authors.forename: Megha
authors.initials: M
authors.lastname: Nivsarkar
authors.forename: Matthew
authors.initials: M
authors.lastname: Themis
authors.forename: Maxine V
authors.initials: MV
authors.lastname: Holder
authors.forename: Suzanne M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: Niraja
authors.initials: N
authors.lastname: Dighe
authors.forename: Alaine T
authors.initials: AT
authors.lastname: Ruthe
authors.forename: Ajay
authors.initials: A
authors.lastname: Mistry
authors.forename: Brian
authors.initials: B
authors.lastname: Bigger
authors.forename: Ahad
authors.initials: A
authors.lastname: Rahim
authors.forename: Tuan H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Charles
authors.initials: C
authors.lastname: Coutelle
mesh_terms: 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