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


ABSTRACT: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based ?-retrovirus vector expressing interleukin-2 receptor ?-chain (?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.We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) ?-retrovirus vector containing deletions in viral enhancer sequences expressing ?c (SIN-?c).All patients received bone marrow-derived CD34+ cells transduced with the SIN-?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.This modified ?-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.).

SUBMITTER: Hacein-Bey-Abina S 

PROVIDER: S-EPMC4274995 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Hacein-Bey-Abina Salima S   Pai Sung-Yun SY   Gaspar H Bobby HB   Armant Myriam M   Berry Charles C CC   Blanche Stephane S   Bleesing Jack J   Blondeau Johanna J   de Boer Helen H   Buckland Karen F KF   Caccavelli Laure L   Cros Guilhem G   De Oliveira Satiro S   Fernández Karen S KS   Guo Dongjing D   Harris Chad E CE   Hopkins Gregory G   Lehmann Leslie E LE   Lim Annick A   London Wendy B WB   van der Loo Johannes C M JC   Malani Nirav N   Male Frances F   Malik Punam P   Marinovic M Angélica MA   McNicol Anne-Marie AM   Moshous Despina D   Neven Benedicte B   Oleastro Matías M   Picard Capucine C   Ritz Jerome J   Rivat Christine C   Schambach Axel A   Shaw Kit L KL   Sherman Eric A EA   Silberstein Leslie E LE   Six Emmanuelle E   Touzot Fabien F   Tsytsykova Alla A   Xu-Bayford Jinhua J   Baum Christopher C   Bushman Frederic D FD   Fischer Alain A   Kohn Donald B DB   Filipovich Alexandra H AH   Notarangelo Luigi D LD   Cavazzana Marina M   Williams David A DA   Thrasher Adrian J AJ  

The New England journal of medicine 20141001 15


<h4>Background</h4>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.<h4>Meth  ...[more]

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