Journal
BLOOD
Volume 116, Issue 6, Pages 900-908Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-10-250209
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Funding
- National Heart, Lung, and Blood Institute [P01 HL 53749]
- Cancer Center [P30 CA 21765]
- Assisi Foundation of Memphis
- American Lebanese Syrian Associated Charities
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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-h gamma(c)-Revgen vector contains the entire human common gamma chain (gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1 alpha-h gamma(c)OPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1 alpha) 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-EF1 alpha-h gamma(c)OPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-h gamma(c)-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1 alpha-h gamma(c)OPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1 alpha-h gamma(c)OPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety. (Blood. 2010;116(6):900-908)
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