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 IL2Rγ 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.

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Persistent URL dx.doi.org/10.1038/sj.mt.6300297, hdl.handle.net/1765/36968
Citation
Pike, K, van der Burg, M, Wagemaker, G, van Dongen, J.J.M, & Staal, F.J.T. (2007). New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Molecular Therapy, 15(11), 1910–1916. doi:10.1038/sj.mt.6300297