A Modified gamma-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency

作者：Hacein-Bey-Abina, S.; Pai, S. -Y.; Gaspar, H. B.; Armant, M.; Berry, C. C.; Blanche, S.; Bleesing, J.; Blondeau, J.; de Boer, H.; Buckland, K. F.; Caccavelli, L.; Cros, G.; De Oliveira, S.; Fernandez, K. S.; Guo, D.; Harris, C. E.; Hopkins, G.; Lehmann, L. E.; Lim, A.; London, W. B.; van der Loo, J. C. M.; Malani, N.; Male, F.; Malik, P.; Marinovic, M. A.; McNicol, A. -M.; Moshous, D.; Neven, B.; Oleastro, M.; Picard, C.; Ritz, J.; Rivat, C.; Schambach, A.; Shaw, K. L.; Sherman, E. A.

来源：New England Journal of Medicine, 2014, 371(15): 1407-1417.

DOI：10.1056/NEJMoa1404588

• HEMATOPOIETIC STEM-CELLS
• SCID-X1 GENE-THERAPY
• DNA INTEGRATION
• TRANSPLANTATION
• DEFICIENCY
• RECONSTITUTION
• SURVIVAL
• MARROW
• SITES
• FATE

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 interleukin-2 receptor gamma-chain (gamma c) complementary DNA successfully restored immunity in most 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 (SIN) gamma-retrovirus vector containing deletions in viral enhancer sequences expressing gamma c (SIN-gamma c). @@@ RESULTS @@@ All patients received bone marrow-derived CD34+ cells transduced with the SIN-gamma c vector, without preparative conditioning. After 12.1 to 38.7 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.

• 出版日期2014-10-9