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Cell culture assays reveal the importance of retroviral vector design for insertional genotoxicity
Abstract
Retroviral vectors with long terminal repeats (LTRs), which contain strong enhancer/promoter sequences at both ends of their genome, are widely used for stable gene transfer into hematopoietic cells. However, recent clinical data and mouse models point to insertional activation of cellular proto-oncogenes as a dose-limiting side effect of retroviral gene delivery that potentially induces leukemia. Self-inactivating (SIN) retroviral vectors do not contain the terminal repetition of the enhancer/promoter, theoretically attenuating the interaction with neighboring cellular genes. With a new assay based on in vitro expansion of primary murine hematopoietic cells and selection in limiting dilution, we showed that SIN vectors using a strong internal retroviral enhancer/promoter may also transform cells by insertional mutagenesis. Most transformed clones, including those obtained after dose escalation of SIN vectors, showed insertions upstream of the third exon of Evi1 and in reverse orientation to its transcriptional orientation. Normalizing for the vector copy number, we found the transforming capacity of SIN vectors to be significantly reduced when compared with corresponding LTR vectors. Additional modifications of SIN vectors may further increase safety. Improved cell-culture assays will likely play an important role in the evaluation of insertional mutagenesis.
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“These severe adverse events are now understood to result from “side effects” of viral integration into the genome.”
From Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia (2009) · cites this paper as [45]
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“Specifically, removing the strong retroviral enhancer/promoter sequences from the LTR and placing the promoter sequence into an internal position (self inactivating (SIN) vector), has been shown to reduce the insertional transformation of target cells in an in vitro immortalization assay. [45].”
From Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia (2009) · cites this paper as [45]
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Cites
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Zychlinski, D., Schambach, A., Modlich, U., Maetzig, T., Meyer, J., Grassman, E., Mishra, A., & Baum, C. (2008) · Molecular Therapy · doi:10.1038/mt.2008.5 · Cited by 271
Self-citationInsertional Gene Activation by Lentiviral and Gammaretroviral Vectors
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Self-citationStem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity
Wu, C., & Dunbar, C. E. (2011) · Frontiers of Medicine · doi:10.1007/s11684-011-0159-1 · Cited by 114
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Brendel, C., Negre, O., Rothe, M., Guda, S., Parsons, G., Harris, C., McGuinness, M., Abriss, D., Tsytsykova, A., Klatt, D., et al. (2020) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.03.015 · Cited by 72
Self-citationThe old and the new: Prospects for non-integrating lentiviral vector technology
Apolonia, L. (2020) · Viruses · doi:10.3390/v12101103 · Cited by 58
The retroviral vector family: something for everyone
Elsner, C., & Bohne, J. (2017) · Virus Genes · doi:10.1007/s11262-017-1489-0 · Cited by 36
Self-citationFinding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia
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Metadata
- Authors
- Modlich, U., Bohne, J., Schmidt, M., von Kalle, C., Knöss, S., Schambach, A., & Baum, C.
- Affiliations
- From the Department of Experimental Hematology, Hannover Medical School, Germany; the Department of Hematology/Oncology and Institute for Molecular Medicine and Cell Research, Albert Ludwig University, Freiburg, Germany; the National Center for Tumor Diseases (NCT), Heidelberg, Germany; and the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-10-15
- Volume
- 108
- Issue
- 8
- Pages
- 2545-2553
- ISSN
- 0006-4971
- 1528-0020
- Cited by
- 278
- References
- 1
- Language
- en
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