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Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning.
Mol Ther. 2011 Oct; 19(10):1867-77.MT

Abstract

Clinical trials have demonstrated the potential of ex vivo hematopoietic stem cell gene therapy to treat X-linked severe combined immunodeficiency (SCID-X1) using γ-retroviral vectors, leading to immune system functionality in the majority of treated patients without pretransplant conditioning. The success was tempered by insertional oncogenesis in a proportion of the patients. To reduce the genotoxicity risk, a self-inactivating (SIN) lentiviral vector (LV) with improved expression of a codon optimized human interleukin-2 receptor γ gene (IL2RG) cDNA (coγc), regulated by its 1.1 kb promoter region (γcPr), was compared in efficacy to the viral spleen focus forming virus (SF) and the cellular phosphoglycerate kinase (PGK) promoters. Pretransplant conditioning of Il2rg(-/-) mice resulted in long-term reconstitution of T and B lymphocytes, normalized natural antibody titers, humoral immune responses, ConA/IL-2 stimulated spleen cell proliferation, and polyclonal T-cell receptor gene rearrangements with a clear integration preference of the SF vector for proto-oncogenes, contrary to the PGK and γcPr vectors. We conclude that SIN lentiviral gene therapy using coγc driven by the γcPr or PGK promoter corrects the SCID phenotype, potentially with an improved safety profile, and that low-dose conditioning proved essential for immune competence, allowing for a reduced threshold of cell numbers required.

Authors+Show Affiliations

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21750532

Citation

Huston, Marshall W., et al. "Correction of Murine SCID-X1 By Lentiviral Gene Therapy Using a Codon-optimized IL2RG Gene and Minimal Pretransplant Conditioning." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 19, no. 10, 2011, pp. 1867-77.
Huston MW, van Til NP, Visser TP, et al. Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. Mol Ther. 2011;19(10):1867-77.
Huston, M. W., van Til, N. P., Visser, T. P., Arshad, S., Brugman, M. H., Cattoglio, C., Nowrouzi, A., Li, Y., Schambach, A., Schmidt, M., Baum, C., von Kalle, C., Mavilio, F., Zhang, F., Blundell, M. P., Thrasher, A. J., Verstegen, M. M., & Wagemaker, G. (2011). Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. Molecular Therapy : the Journal of the American Society of Gene Therapy, 19(10), 1867-77. https://doi.org/10.1038/mt.2011.127
Huston MW, et al. Correction of Murine SCID-X1 By Lentiviral Gene Therapy Using a Codon-optimized IL2RG Gene and Minimal Pretransplant Conditioning. Mol Ther. 2011;19(10):1867-77. PubMed PMID: 21750532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. AU - Huston,Marshall W, AU - van Til,Niek P, AU - Visser,Trudi P, AU - Arshad,Shazia, AU - Brugman,Martijn H, AU - Cattoglio,Claudia, AU - Nowrouzi,Ali, AU - Li,Yuedan, AU - Schambach,Axel, AU - Schmidt,Manfred, AU - Baum,Christopher, AU - von Kalle,Christof, AU - Mavilio,Fulvio, AU - Zhang,Fang, AU - Blundell,Mike P, AU - Thrasher,Adrian J, AU - Verstegen,Monique M A, AU - Wagemaker,Gerard, Y1 - 2011/07/12/ PY - 2011/7/14/entrez PY - 2011/7/14/pubmed PY - 2012/2/4/medline SP - 1867 EP - 77 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 19 IS - 10 N2 - Clinical trials have demonstrated the potential of ex vivo hematopoietic stem cell gene therapy to treat X-linked severe combined immunodeficiency (SCID-X1) using γ-retroviral vectors, leading to immune system functionality in the majority of treated patients without pretransplant conditioning. The success was tempered by insertional oncogenesis in a proportion of the patients. To reduce the genotoxicity risk, a self-inactivating (SIN) lentiviral vector (LV) with improved expression of a codon optimized human interleukin-2 receptor γ gene (IL2RG) cDNA (coγc), regulated by its 1.1 kb promoter region (γcPr), was compared in efficacy to the viral spleen focus forming virus (SF) and the cellular phosphoglycerate kinase (PGK) promoters. Pretransplant conditioning of Il2rg(-/-) mice resulted in long-term reconstitution of T and B lymphocytes, normalized natural antibody titers, humoral immune responses, ConA/IL-2 stimulated spleen cell proliferation, and polyclonal T-cell receptor gene rearrangements with a clear integration preference of the SF vector for proto-oncogenes, contrary to the PGK and γcPr vectors. We conclude that SIN lentiviral gene therapy using coγc driven by the γcPr or PGK promoter corrects the SCID phenotype, potentially with an improved safety profile, and that low-dose conditioning proved essential for immune competence, allowing for a reduced threshold of cell numbers required. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/21750532/Correction_of_murine_SCID_X1_by_lentiviral_gene_therapy_using_a_codon_optimized_IL2RG_gene_and_minimal_pretransplant_conditioning_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(16)32779-4 DB - PRIME DP - Unbound Medicine ER -