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

Abstract

BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), 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-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) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ 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 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 γ-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.)

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

“…At least 20 genes have been associated with SCID [1]. Currently, curative treatments such as hematopoietic stem cell transplantation (HSCT) [2][3][4] and gene therapy [5][6][7] can improve a patient's outcome if the treatment can be initiated before severe infections occur. Previously, a significant number of children with SCID would die before a diagnosis was made [8] or before a curative treatment could be administered [2,9,10].…”

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

“…Lentiviral targeted hematopoietic stem cell (HSC) gene therapy has recently achieved steadily accelerating progress for the treatment of hematological diseases, [1][2][3] which includes hemoglobinopathies (sickle cell disease and b-thalassemia). [4][5][6][7] The first clinical trial for b-thalassemia was initiated in 2007.…”

Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients

“…To shed light on this issue in our trial, we used sequence readcounts to estimate the relative abundances of clones with integrations near a set known leukemiarelated genes generated in another study and near a set of genes homologous to retrovirally tagged cancer gene database (RTCGD) mouse genes identified in hematopoietic cancers caused by retroviral and transposon mutagenesis. 38,39 We compared these estimates with those of all other clones for both gene sets of interest. In both cases, we found that clones with ISs near genes of interest were statistically more abundant, as indicated by the average proportion of sequence reads they accounted for within samples (supplemental Figure 3).…”