© The American Society of Gene & Cell Therapy editorial the investigators, and through a news article in Science—that a relative clonal dominance occurred in a patient treated with gene therapy for a form of β-thalassemia. 14 The patient was treated in June 2007 with autologous CD34+ cells transduced with a lentiviral vector encoding a variant β-globin gene transcribed from a promoter under the control of a strong erythroid enhancer. The dominant clone that emerged approximately a year after transplant contained an activating insertion within the HMGA2 proto-oncogene. Aberrant expression of HMGA2 was likely caused by the erythroid enhancer carried by the vector. Although this clone comprises approximately one half of the progeny of the transduced cells, its abundance has been stable for many months since being discovered, implying that the clone is benign. Importantly, the patient is transfusion independent and exhibits no evidence of hematologic abnormality. At this point, cause, effect, and clinical significance remain unclear and the field awaits more details in a peer-reviewed format about this important trial and its implications for lentiviral vector safety. It seems reasonable to conclude for now that we need results from additional patients treated with lentiviral vector gene transfer before we can draw solid conclusions regarding the relative safety of this vector system. In this regard, two new upcoming trials for SCID-X1 that have recently undergone review by the Recombinant DNA Advisory Committee should prove highly informative (http://oba. od. nih. gov/oba/RAC/meetings/dec2008/RAC_Minutes_12-08. pdf; http://oba. od. nih. gov/oba/RAC/meetings/mar2009/March% 202009% 20minutes. pdf). Both trials propose the use of vectors devoid of viral LTRs or strong enhancers, which clearly elevate genotoxic risk. Building on recent improvements in the design of SIN γ-retroviral vectors that can be produced with effective titers, 15 one trial proposes the use of a SIN MLV-based γ-retroviral vector that utilizes the elongation factor (EF)-1α cellular promoter to direct transgene expression. Recent preclinical studies have shown that such a design results in a vector that compares favorably to a lentiviral vector in genotoxicity studies and gives rise to significantly reduced clustering of integration sites at TFBS-rich regions in the genome. 10, 16 The second trial proposes to use a SIN lentiviral vector that incorporates an insulator element and also exploits the EF-1α promoter to drive gene expression. Comparisons of clinical outcomes and insertion-site profiles will be interesting and most assuredly instructive.

Currently, the strategy of these trials to eliminate enhancer sequences from the vector would seem to be the best approach to minimize genotoxicity of vector integration. However, this is dependent upon the ability to achieve therapeutic transgene expression in the target cells using a promoter of relatively weak to moderate strength. For disorders in which high-level transgene expression is required for a therapeutic effect (eg, β-thalassemia), inclusion of some type of enhancer element in the vector will be unavoidable. One potential solution to minimize the risk of such