Integration and the Risk of Insertional Mutagenesis

The potential for a deleterious outcome following retroviral vector insertion has always been acknowledged. Before 2002, the only example of unintentional tumor production in a ret-roviral gene transfer experiment in large animals occurred when 3 cases of lymphoma were reported among 10 Rhesus monkeys that had received myeloablative irradiation and then been transplanted with hematopoietic stem cells that had been exposed to a large number of RCR, together with the experimental vector. Subsequent analyses revealed that the cancers resulted from integration of an RCR (not the original retroviral vector), were clonal events, and developed only after long periods (6-7 months) of retroviremia (73,74). In addition, analysis of vector integration sites in 1 of the original 2 ADA patients (A.D.), 10 years after she received 11 separate infusions of retroviral vector-transduced peripheral blood lymphocytes, revealed polyclonal integrations sites, even in a subset of T cells that appeared to have expanded in vivo since that time (3).

However, the news that two children treated in a French gene therapy trial for severe combined immunodeficiency (SCID)-XI (75) has developed leukemia is a worrying development. Furthermore, the integration site of the vector in the leukemic cells are near a known oncogene, LMO2. This is a very clear demonstration of the risk inherent in using integrating vectors.

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