Retroviral vector designs under clinical evaluation. (A) LTR-driven γ-RV, exemplified by the MFG/SFG vector design used in X-SCID and WAS clinical trials. (B) SIN-γ-RV, exemplified by the SRS11 EFS vector design used in the X-SCID consortium trial. (C) Nonspecific SIN-LV, exemplified by the MND-ALD vector design used in the ALD trial. (D) Lineage-restricted SIN-LV, exemplified by the TNS9.3 vector for the treatment of β-thalassemia major. U3 E/P indicates retroviral enhancer/promoter from the LTR U3 region; PRE/WPRE (woodchuck hepatitis), posttranscriptional regulatory element; SIN, self-inactivating vector design (▿ represents U3 deletion); specificity: − indicates ubiquitous; and +, lineage-specific; LCR, locus control region; and HBB, human β-globin gene. Green represents retroviral enhancer/promoter elements; and red, mammalian enhancer/promoter elements.