title: New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy.
abstract: The oncogenic potential of retrovirus-mediated gene therapy has been re-emphasized because four patients developed T-cell acute lymphoblastic leukemia (T-ALL)-like disease from an otherwise successful gene therapy trial for X-linked severe combined immunodeficiency (X-linked SCID). X-linked SCID, a disease caused by inactivating mutations in the IL2Rgamma gene, is part of a heterogeneous group of SCIDs characterized by the lack of T cells in conjunction with the absence of B and/or natural killer (NK) cells. Gene therapy approaches are being developed for this group of diseases. In this review we discuss the various forms of SCID in relation to normal T-cell development. In addition, we consider the possible role of LMO2 and other T-ALL oncogenes in the development of adverse effects as seen in the X-linked SCID gene therapy trial. Furthermore, we debate whether the integration near the LMO2 locus is sufficient to result in T-ALL-like proliferations or whether the gamma-retroviral viral expression of the therapeutic IL2RG gene contributes to leukemogenesis. Finally, we review some newly developed murine models that may have added value for gene therapy safety studies.
authors.affiliation: Department of Immunology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Pike-Overzet
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Gerard
authors.initials: G
authors.lastname: Wagemaker
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D015316:Genetic Therapy; D006801:Humans; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*