A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

[severe combined immunodeficiency]

In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID -X 1 ), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc ) 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 -X 1 .We enrolled nine boys with SCID -X 1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN ) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc ).All patients received bone marrow-derived CD 34 + cells transduced with the SIN-γc 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 CD 3 + 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 LMO 2 , MECOM , and other lymphoid proto-oncogenes in our patients .This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID -X 1 . The long -term effect of this therapy on leukemogenesis remains unknown . (Funded by the National Institutes of Health and others ; ClinicalTrials .gov numbers , NCT 01410019 , NCT 01175239 , and NCT 01129544 .).