The development of gene therapy has been hampered by safety issues, such as the risk of oncogenic insertion of the vectors used to deliver the therapeutic gene. A new trial could help put gene therapy back on track, as it showed that a self-inactivating (SIN) γ-retrovirus-based therapy can restore immunity in patients with X-linked severe combined immunodeficiency (X-SCID), and that no vector-induced leukaemias were observed in these individuals after a median follow-up of 33 months (N. Engl. J. Med. 371, 1407–1417; 2014).
Individuals with X-SCID, which is caused by mutations in the gene encoding the interleukin-2 receptor γ-chain (IL2RG), are at high risk of fatal infections early in life unless they receive a haematopoietic stem cell transplantation (HSCT), ideally from a matched donor. At the beginning of this century, trials of first-generation gene therapy that used γ-retroviral vectors to deliver IL2RG successfully restored immunity in individuals with X-SCID. Unfortunately, insertion of the vector upstream of oncogenes increased oncogene expression, leading to the clonal expansion of malignant cells and T-cell acute lymphoblastic leukaemia in 25% of patients, with a median latency of 33 months.
