A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells
Open accessAbstract
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-hγc-Revgen vector contains the entire human common γ chain (γc) genomic sequence driven by the γc promoter. The CL20i4-EF1α-hγcOPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1α) gene to express a codon-optimized human γc cDNA. Both vectors contain a 400-bp insulator fragment from the chicken β-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-EF1α-hγcOPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-hγc-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1α-hγcOPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1α-hγcOPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety.
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Reduced transgene expression of NILVs can be amended by using strong enhancers or promoters that produce sufficient transgene expression.
“This can be amended by using strong enhancers or promoters that can produce sufficient transgene expression [70,71,72].”
From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [71]
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- Authors
- 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.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and
- Hôpital Necker-Enfants Malades (FR)
- Inserm U768, Université René Descartes and Hôpital Necker-Enfants Malades, Paris, France
- National Institutes of Health (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-08-12
- Volume
- 116
- Issue
- 6
- Pages
- 900-908
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2924228
- OpenAlex
- W2031377099
- Cited by
- 119
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 9 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 12 · 2014: 13 · 2013: 12 · 2012: 17
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Assisi Foundation of Memphis
- American Lebanese Syrian Associated Charities (CA 21765)
- National Heart, Lung, and Blood Institute (P01HL053749, P01HL53749)
- National Cancer Institute (P 30CA 21765, P30CA021765)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- self-inactivating lentiviral vectors, X-linked severe combined immunodeficiency, common gamma chain, EF1α promoter, codon optimization, T cell development, bone marrow transplantation, vector safety, tumor formation
- MeSH terms
- Animals, B-Lymphocytes, Cell Transformation, Neoplastic, DNA-Binding Proteins, Female, Genetic Vectors, Humans, Introns, Killer Cells, Natural, Metalloproteins, Mice, Mutant Strains, Promoter Regions, Genetic, T-Lymphocytes, Genetic Therapy, Bone Marrow Transplantation, Lentivirus, Severe Combined Immunodeficiency, Mice, SCID, Antigens, CD34, Jurkat Cells, Peptide Elongation Factor 1, Adaptor Proteins, Signal Transducing, Mice, Interleukin Receptor Common gamma Subunit, LIM Domain Proteins
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