The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Physiological Promoters Reduce the Genotoxic Risk of Integrating Gene Vectors
Open accessAbstract
The possible activation of cellular proto-oncogenes as a result of clonal transformation is a potential limitation in a therapeutic approach involving random integration of gene vectors. Given that enhancer promiscuity represents an important mechanism of insertional transformation, we assessed the enhancer activities of various cellular and retroviral promoters in transient transfection assays, and also in a novel experimental system designed to measure the activation of a minigene cassette contained in stably integrating retroviral vectors. Retroviral enhancer-promoters showed a significantly greater potential to activate neighboring promoters than did cellular promoters derived from human genes, elongation factor-1alpha (EF1alpha) and phosphoglycerate kinase (PGK). Self-inactivating (SIN) vector design reduced but did not abolish enhancer interactions. Using a recently established cell culture assay that detects insertional transformation by serial replating of primary hematopoietic cells, we found that SIN vectors containing the EF1alpha promoter greatly decrease the risk of insertional transformation. Despite integration of multiple copies per cell, activation of the crucial proto-oncogene Evi1 was not detectable when using SIN-EF1alpha vectors. On the basis of several quantitative indicators, the decrease in transforming activity was highly significant (more than tenfold, P < 0.01) when compared with similarly designed vectors containing a retroviral enhancer-promoter with or without a well-characterized genetic insulator core element. In this manner, the insertional biosafety of therapeutic gene vectors can be greatly enhanced and proactively evaluated in sensitive cell-based assays.
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“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 [72]
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Cites
LMO2 -Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M. P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C. S., Pawliuk, R., Morillon, E., et al. (2003) · Science · doi:10.1126/science.1088547 · Cited by 3,587
Plat-E: an efficient and stable system for transient packaging of retroviruses
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The protein CTCF is required for the enhancer blocking activity of vertebrate insulators
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Montini, E., Cesana, D., Schmidt, M., Sanvito, F., Ponzoni, M., Bartholomae, C. C., Sergi, L. S., Benedicenti, F., Ambrosi, A., Serio, C. D., et al. (2006) · Nature Biotechnology · doi:10.1038/nbt1216 · Cited by 709
Murine Leukemia Induced by Retroviral Gene Marking
Li, Z., Düllmann, J., Schiedlmeier, B., Schmidt, M., Kalle, C. V., Meyer, J., Forster, M., Stocking, C., Wahlers, A., Frank, O., et al. (2002) · Science · doi:10.1126/science.1068893 · Cited by 653
Self-citationTannock, I. F., Hill, R. P., & Carey, R. W. (1989) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-198905000-00037 · Cited by 473
Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity
Modlich, U., Bohne, J., Schmidt, M., Kalle, C. V., Knöß, S., Schambach, A., & Baum, C. (2006) · Blood · doi:10.1182/blood-2005-08-024976 · Cited by 326
Self-citationClonal Dominance of Hematopoietic Stem Cells Triggered by Retroviral Gene Marking
Kustikova, O. S., Fehse, B., Modlich, U., Yang, M., Düllmann, J., Kamino, K., Neuhoff, N. V., Schlegelberger, B., Li, Z., & Baum, C. (2005) · Science · doi:10.1126/science.1105063 · Cited by 323
Self-citationGenotoxicity of Retroviral Integration In Hematopoietic Cells
Nienhuis, A. W., Dunbar, C. E., & Sorrentino, B. P. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.03.001 · Cited by 301
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Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., Clappier, E., Caccavelli, L., Delabesse, E., Beldjord, K., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35700 · Cited by 1,854
Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
Biffi, A., Montini, E., Lorioli, L., Cesani, M., Fumagalli, F., Plati, T., Baldoli, C., Martino, S., Calabria, A., Canale, S., et al. (2013) · Science · doi:10.1126/science.1233158 · Cited by 1,180
Gene therapy returns to centre stage
Naldini, L. (2015) · Nature · doi:10.1038/nature15818 · Cited by 1,184
Montini, E., Cesana, D., Schmidt, M., Sanvito, F., Bartholomae, C. C., Ranzani, M., Benedicenti, F., Sergi, L. S., Ambrosi, A., Ponzoni, M., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37630 · Cited by 571
Heckl, D., Kowalczyk, M. S., Yudovich, D., Belizaire, R., Puram, R. V., McConkey, M. E., Thielke, A., Aster, J. C., Regev, A., & Ebert, B. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2951 · Cited by 555
Metadata
- Authors
- Zychlinski, D., Schambach, A., Modlich, U., Maetzig, T., Meyer, J., Grassman, E., Mishra, A., & Baum, C.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Baum, Christopher
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 16
- Issue
- 4
- Pages
- 718-725
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W1971410311
- Cited by
- 271
- References
- 34
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 9 · 2019: 8 · 2018: 12 · 2017: 15 · 2016: 12 · 2015: 16 · 2014: 14 · 2013: 23 · 2012: 18
- FWCI
- 18.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA107492)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- retroviral vectors, enhancer-promoter interactions, self-inactivating vectors, EF1α promoter, PGK promoter, EVI1, proto-oncogene activation, hematopoietic cells
- MeSH terms
- MDS1 and EVI1 Complex Locus Protein, Proto-Oncogene Mas, Animals, Bone Marrow Cells, Cell Line, Cells, Cultured, DNA-Binding Proteins, Enhancer Elements, Genetic, Fibroblasts, Genetic Vectors, Humans, Mice, Inbred C57BL, Phosphoglycerate Kinase, Promoter Regions, Genetic, Proto-Oncogenes, Retroviridae, Transcription Factors, Transfection, Mutagenesis, Insertional, Peptide Elongation Factor 1, Mice
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