A Self-Inactivating Gamma-Retrovirus Vector for Severe Combined Immunodeficiency

Background In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based gamma-retrovirus vector expressing the interleukin-2 receptor gamma-chain complementary DNA successfully restored immunity in all patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. Methods We enrolled nine boys with SCID-X1 in parallel trials, in Europe and the United States, to evaluate treatment with a self-inactivating gamma-retrovirus (SIN-gamma-c) vector containing deletions in viral enhancer sequences. Results All patients received bone marrow-derived CD34+ cells transduced with the SIN-gamma-c vector, without preparative conditioning. After 12 to 38 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. Conclusions This modified gamma-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)