In 1990, the first clinical trial to deliver a therapeutic gene was conducted.5 A gamma-retroviral vector was used to mediate the transfer of the gene encoding adenosine deaminase (ADA) into the T cells of two children suffering from severe combined immunodeficiency (SCID)6, a rare condition caused by loss-of-function mutations in the genes encoding the interleukin-2 receptor gamma subunit or ADA.7,8 Authors concluded that gene therapy was a safe and effective treatment for some patients with this severe immunodeficiency disease.6

In the late 1990s and early 2000s, trials continued to demonstrate unequivocal improvement in immune function in patients with SCID. However, several years after treatment, patients in the X-linked SCID trials, as well as those for chronic granulomatous disease and Wiskott–Aldrich syndrome, developed acute myeloid and lymphoid leukemias; this was due to activation of proto-oncogenes adjacent to proviral insertions, which were linked to strong enhancers present in gamma-retroviral vectors, and the propensity of these vectors to insert near promoters.7