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Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency

Poletti, V; Charrier, S; Corre, G; Gjata, B; Vignaud, A; Zhang, F; Rothe, M; ... Mavilio, F; + view all (2018) Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. Molecular Therapy - Methods and Clinical Development , 9 pp. 257-269. 10.1016/j.omtm.2018.03.002. Green open access

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Abstract

X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the interleukin-2 receptor γ chain gene (IL2RG), and it is characterized by profound defects in T, B, and natural killer (NK) cell functions. Transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically corrected with early murine leukemia retrovirus (MLV)-derived gammaretroviral vectors showed restoration of T cell immunity in patients, but it resulted in vector-induced insertional oncogenesis. We developed a self-inactivating (SIN) lentiviral vector carrying a codon-optimized human IL2RG cDNA driven by the EF1α short promoter (EFS-IL2RG), and we tested its efficacy and safety in vivo by transplanting transduced Il2rg-deficient Lin- HSPCs in an Il2rg-/-/Rag2-/- mouse model. The study showed restoration of T, B, and NK cell counts in bone marrow and peripheral blood and normalization of thymus and spleen cellularity and architecture. High-definition insertion site analysis defined the EFS-IL2RG genomic integration profile, and it showed no sign of vector-induced clonal selection or skewing in primarily and secondarily transplanted animals. The study enables a phase I/II clinical trial aimed at restoring both T and B cell immunity in SCID-X1 children upon non-myeloablative conditioning.

Type: Article
Title: Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtm.2018.03.002
Publisher version: http://dx.doi.org/10.1016/j.omtm.2018.03.002
Language: English
Additional information: © 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: SCID-X1, gene therapy, genotoxicity, immunodeficiency, integration, lentiviral vector
URI: http://discovery.ucl.ac.uk/id/eprint/10048293
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