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A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells.
Blood. 2010 Aug 12; 116(6):900-8.Blood

Abstract

To develop safer and more effective vectors for gene therapy of X-linked severe combined immunodeficiency (SCID-X1), we have evaluated new self-inactivating lentiviral vectors based on the HIV virus. The CL20i4-hgamma(c)-Revgen vector contains the entire human common gamma chain (gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1alpha-hgamma(c)OPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1alpha) gene to express a codon-optimized human gamma(c) cDNA. Both vectors contain a 400-bp insulator fragment from the chicken beta-globin locus within the self-inactivating long-terminal repeat. Transduction of bone marrow cells using either of these vectors restored T, B, and natural killer lymphocyte development and function in a mouse SCID-X1 transplantation model. Transduction of human CD34(+) bone marrow cells from SCID-X1 patients with either vector restored T-cell development in an in vitro assay. In safety studies using a Jurkat LMO2 activation assay, only the CL20i4-EF1alpha-hgamma(c)OPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-hgamma(c)-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1alpha-hgamma(c)OPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1alpha-hgamma(c)OPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety.

Authors+Show Affiliations

Division of Experimental Hematology, Department of Hematology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, TN 38105, USA. sheng.zhou@stjude.orgNo 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, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20457870

Citation

Zhou, Sheng, et al. "A Self-inactivating Lentiviral Vector for SCID-X1 Gene Therapy That Does Not Activate LMO2 Expression in Human T Cells." Blood, vol. 116, no. 6, 2010, pp. 900-8.
Zhou S, Mody D, DeRavin SS, et al. A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood. 2010;116(6):900-8.
Zhou, S., Mody, D., DeRavin, S. S., Hauer, J., Lu, T., Ma, Z., Hacein-Bey Abina, S., Gray, J. T., Greene, M. R., Cavazzana-Calvo, M., Malech, H. L., & Sorrentino, B. P. (2010). A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood, 116(6), 900-8. https://doi.org/10.1182/blood-2009-10-250209
Zhou S, et al. A Self-inactivating Lentiviral Vector for SCID-X1 Gene Therapy That Does Not Activate LMO2 Expression in Human T Cells. Blood. 2010 Aug 12;116(6):900-8. PubMed PMID: 20457870.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. AU - Zhou,Sheng, AU - Mody,Disha, AU - DeRavin,Suk See, AU - Hauer,Julia, AU - Lu,Taihe, AU - Ma,Zhijun, AU - Hacein-Bey Abina,Salima, AU - Gray,John T, AU - Greene,Michael R, AU - Cavazzana-Calvo,Marina, AU - Malech,Harry L, AU - Sorrentino,Brian P, Y1 - 2010/05/10/ PY - 2010/5/12/entrez PY - 2010/5/12/pubmed PY - 2010/9/18/medline SP - 900 EP - 8 JF - Blood JO - Blood VL - 116 IS - 6 N2 - To develop safer and more effective vectors for gene therapy of X-linked severe combined immunodeficiency (SCID-X1), we have evaluated new self-inactivating lentiviral vectors based on the HIV virus. The CL20i4-hgamma(c)-Revgen vector contains the entire human common gamma chain (gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1alpha-hgamma(c)OPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1alpha) gene to express a codon-optimized human gamma(c) cDNA. Both vectors contain a 400-bp insulator fragment from the chicken beta-globin locus within the self-inactivating long-terminal repeat. Transduction of bone marrow cells using either of these vectors restored T, B, and natural killer lymphocyte development and function in a mouse SCID-X1 transplantation model. Transduction of human CD34(+) bone marrow cells from SCID-X1 patients with either vector restored T-cell development in an in vitro assay. In safety studies using a Jurkat LMO2 activation assay, only the CL20i4-EF1alpha-hgamma(c)OPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-hgamma(c)-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1alpha-hgamma(c)OPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1alpha-hgamma(c)OPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/20457870/A_self_inactivating_lentiviral_vector_for_SCID_X1_gene_therapy_that_does_not_activate_LMO2_expression_in_human_T_cells_ L2 - https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2009-10-250209 DB - PRIME DP - Unbound Medicine ER -