Tags

Type your tag names separated by a space and hit enter

Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency.
Mol Ther Methods Clin Dev. 2018 Jun 15; 9:257-269.MT

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.

Authors+Show Affiliations

Genethon, Evry, France.Genethon, Evry, France.Genethon, Evry, France.Genethon, Evry, France.Genethon, Evry, France.University College London, Great Ormond Street Institute of Child Health, London, UK.Institute of Experimental Hematology, Hannover Medical School (MHH), Hannover, Germany.Institute of Experimental Hematology, Hannover Medical School (MHH), Hannover, Germany.University College London, Great Ormond Street Institute of Child Health, London, UK.University College London, Great Ormond Street Institute of Child Health, London, UK.Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. Imagine Institute, Paris Descartes-Sorbonne Cité University, Paris, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29707600

Citation

Poletti, Valentina, et al. "Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency." Molecular Therapy. Methods & Clinical Development, vol. 9, 2018, pp. 257-269.
Poletti V, Charrier S, Corre G, et al. Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. Molecular therapy. Methods & clinical development. 2018;9:257-269.
Poletti, V., Charrier, S., Corre, G., Gjata, B., Vignaud, A., Zhang, F., Rothe, M., Schambach, A., Gaspar, H. B., Thrasher, A. J., & Mavilio, F. (2018). Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. Molecular Therapy. Methods & Clinical Development, 9, 257-269. https://doi.org/10.1016/j.omtm.2018.03.002
Poletti V, et al. Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. Molecular therapy. Methods & clinical development. 2018 Jun 15;9:257-269. PubMed PMID: 29707600.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. AU - Poletti,Valentina, AU - Charrier,Sabine, AU - Corre,Guillaume, AU - Gjata,Bernard, AU - Vignaud,Alban, AU - Zhang,Fang, AU - Rothe,Michael, AU - Schambach,Axel, AU - Gaspar,H Bobby, AU - Thrasher,Adrian J, AU - Mavilio,Fulvio, Y1 - 2018/03/10/ PY - 2017/10/21/received PY - 2018/03/06/accepted PY - 2018/5/1/entrez PY - 2018/5/1/pubmed PY - 2018/5/1/medline KW - SCID-X1 KW - gene therapy KW - genotoxicity KW - immunodeficiency KW - integration KW - lentiviral vector SP - 257 EP - 269 JF - Molecular therapy. Methods & clinical development VL - 9 N2 - 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. SN - 2329-0501 UR - https://www.unboundmedicine.com/medline/citation/29707600/Preclinical_Development_of_a_Lentiviral_Vector_for_Gene_Therapy_of_X_Linked_Severe_Combined_Immunodeficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2329-0501(18)30026-3 DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.