Solving the Problem of γ-Retroviral Vectors Containing Long Terminal Repeats

Results from a clinical gene transfer trial for the X-linked hematological disorder Wiskott–Aldrich syndrome (WAS), carried out by Klein and colleagues at Hannover Medical School in Germany, were reported in the 11 November 2010 issue of the New England Journal of Medicine.1 The article described the clinical outcome and three-year follow-up of two young boys treated with autologous CD34+ cells transduced with a γ-retroviral vector encoding the WAS protein. Following submyeloablative conditioning, long-term engraftment levels of vector-modified CD34+ cells of 9% and 20% were observed in the bone marrow of the two patients, with similar or higher levels of corrected cells found in multiple peripheral blood hematopoietic lineages. Correction of immune abnormalities as well as resolution of autoimmunity and thrombocytopenia were observed in both patients. Although this was a remarkable success, almost as important was the announcement by the investigators in a press release,2 but absent from the publication, that one of what is now a total of 10 treated patients has developed an acute T-cell leukemia related to a vector insertion. Of note, in the New England Journal of Medicine article, significant clonal imbalances were reported for both patients, with clones observed with increased frequency having insertions in proto-oncogenes such as LMO2, MDS/EVI1, PRDM16, and CCND2. This WAS trial thus combines the insertional risk profile reported for the induction of myelodysplastic syndromes (connected with MDS/EVI1) and acute lymphoblastic leukemia (LMO2, CCND2) in previous clinical trials to correct chronic granulomatous disease and X-linked severe combined immunodeficiency (X-SCID).3,4