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.

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.; Schambach, A.; Gaspar, H. B.; Thrasher, A. J.; Mavilio, F.. - In: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT. - ISSN 2329-0501. - 9:(2018), pp. 257-269. [10.1016/j.omtm.2018.03.002]

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

Poletti V.;Mavilio F.
2018

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.
2018
9
257
269
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.; Schambach, A.; Gaspar, H. B.; Thrasher, A. J.; Mavilio, F.. - In: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT. - ISSN 2329-0501. - 9:(2018), pp. 257-269. [10.1016/j.omtm.2018.03.002]
Poletti, V.; Charrier, S.; Corre, G.; Gjata, B.; Vignaud, A.; Zhang, F.; Rothe, M.; Schambach, A.; Gaspar, H. B.; Thrasher, A. J.; Mavilio, F....espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1199462
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