Oncogenesis Following Delivery of a Nonprimate Lentiviral Gene Therapy Vector to Fetal and Neonatal Mice
Open accessAbstract
Gene therapy by use of integrating vectors carrying therapeutic transgene sequences offers the potential for a permanent cure of genetic diseases by stable vector insertion into the patients' chromosomes. However, three cases of T cell lymphoproliferative disease have been identified almost 3 years after retrovirus gene therapy for X-linked severe combined immune deficiency. In two of these cases vector insertion into the LMO2 locus was implicated in leukemogenesis, demonstrating that a more profound understanding is required of the genetic and molecular effects imposed on the host by vector integration or transgene expression. In vivo models to test for retro- and lentiviral vector safety prior to clinical application are therefore needed. Here we present a high incidence of lentiviral vector-associated tumorigenesis following in utero and neonatal gene transfer in mice. This system may provide a highly sensitive model to investigate integrating vector safety prior to clinical application.
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In 2005, one study reported a high incidence of lentiviral-vector-associated tumorigenesis following in utero and neonatal gene transfer in mice.
“In 2005, one study reported a high incidence of lentiviral-vector-associated tumorigenesis following in utero and neonatal gene transfer in mice [7].”
From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [7]
Lentiviral vectors can also insert near oncogenes, and tumor formation has been noted in at least one model that used a non-primate lentivirus-derived vector to transduce embryonic cells.
“Lentiviral vectors can also insert near oncogenes, and tumor formation has been noted in at least one model that used a non-primate lentivirus-derived vector to transduce embryonic cells [50].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [50]
Cites
Kingsman, S. M., Mitrophanous, K., & Olsen, J. C. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302417 · Cited by 84 · see citing works
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Clinical use of lentiviral vectors
Milone, M. C., & O’Doherty, U. (2018) · Leukemia · doi:10.1038/s41375-018-0106-0 · Cited by 930 · see citing works
“Lentiviral vectors can also insert near oncogenes, and tumor formation has been noted in at least one model that used a non-primate lentivirus-derived vector to transduce embryonic cells [50].”
BackgroundThe blood-brain barrier: Physiology and strategies for drug delivery
Pandit, R., Chen, L., & Götz, J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.11.009 · Cited by 651 · see citing works
Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy
Chandler, R. J., LaFave, M. C., Varshney, G. K., Trivedi, N. S., Carrillo-Carrasco, N., Senac, J. S., Wu, W., Hoffmann, V., Elkahloun, A. G., Burgess, S. M., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79213 · Cited by 403 · see citing works
Lentiviral Vectors in Gene Therapy: Their Current Status and Future Potential
Escors, D., & Breckpot, K. (2010) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-010-0063-4 · Cited by 344 · see citing works
Philippe, S., Sarkis, C., Barkats, M., Mammeri, H., Ladroue, C., Petit, C., Mallet, J., & Serguera, C. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606197103 · Cited by 249 · see citing works
Biosafety Features of Lentiviral Vectors
Schambach, A., Zychlinski, D., Ehrnstroem, B., & Baum, C. (2013) · Human Gene Therapy · doi:10.1089/hum.2012.229 · Cited by 173 · see citing works
Liver-directed lentiviral gene therapy in a dog model of hemophilia B
Cantore, A., Ranzani, M., Bartholomae, C. C., Volpin, M., Valle, P. D., Sanvito, F., Sergi, L. S., Gallina, P., Benedicenti, F., Bellinger, D., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa1405 · Cited by 158 · see citing works
Self-citationMethods for Gene Transfer to the Central Nervous System
Kantor, B., Bailey, R. M., Wimberly, K., Kalburgi, S. N., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00003-2 · Cited by 109 · see citing works
Argyros, O., Wong, S. P., Niceta, M., Waddington, S. N., Howe, S. J., Coutelle, C., Miller, A. D., & Harbottle, R. P. (2008) · Gene Therapy · doi:10.1038/gt.2008.113 · Cited by 96 · see citing works
Self-citationClinical Applications Involving CNS Gene Transfer
Kantor, B., McCown, T., Leone, P., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00002-0 · Cited by 74 · see citing works
Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through
Gurumoorthy, N., Nordin, F., Tye, G. J., Wan Kamarul Zaman, W. S., & Ng, M. H. (2022) · Biomedicines · doi:10.3390/biomedicines10010107 · Cited by 69 · see citing works
“In 2005, one study reported a high incidence of lentiviral-vector-associated tumorigenesis following in utero and neonatal gene transfer in mice [7].”
BackgroundInfluential
- Authors
- Themis, M., Waddington, S. N., Schmidt, M., von Kalle, C., Wang, Y., Al-Allaf, F., Gregory, L. G., Nivsarkar, M., Themis, M., Holder, M. V., Buckley, S. M. K., Dighe, N., Ruthe, A. T., Mistry, A., Bigger, B., Rahim, A., Nguyen, T. H., Trono, D., Thrasher, A. J., & Coutelle, C.
- Affiliations
- Imperial College London (GB)
- University of Freiburg (DE)
- Queen Mary University of London (GB)
- University of Geneva (CH)
- Corresponding author
- Themis, Mike
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 12
- Issue
- 4
- Pages
- 763-771
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2172293798
- Cited by
- 243
- References
- 1
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 4 · 2015: 7 · 2014: 10 · 2013: 14 · 2012: 19
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion)
- 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
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Keywords
- lentiviral vectors, gene therapy safety, carcinogenesis, vector integration, in utero gene transfer, fetal mice, T-cell lymphoproliferative disease, LMO2, retroviral gene therapy
- MeSH terms
- Animals, Animals, Newborn, Fetus, Genetic Vectors, Liver, Liver Neoplasms, Mice, Transgenic, Genetic Therapy, HIV-1, Lentivirus, Gene Transfer Techniques, Mice
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