Insertional mutagenesis and development of malignancies induced by integrating gene delivery systems: Implications for the design of safer gene-based interventions in patients
Abstract
Effective gene-based interventions for the treatment of genetic disorders, neurodegenerative diseases and cardiovascular maladies require longterm transgene expression in target cells. Integrating viral vector systems based on the genera of the retroviridae and on adeno-associated virus are suitable tools, as the integration of viral vector genomes into the cellular chromosomal DNA allows for a more stable and long-lasting transgene expression than episomal gene-delivery models. Two nonviral gene-delivery systems with integrating properties have also been developed. These are based on the Sleeping Beauty DNA transposon system and on the Streptomyces bacteriophage integrase phiC31. However, the integration of recombinant vector systems may damage the natural genetic arrangement of the target cell. Such genetic alterations are termed insertional mutagenesis, which might result in malignant cell transformation. Insertional mutagenesis caused leukemia in five patients who participated in clinical trials for the treatment of severe combined immunodeficiency (SCID)-X1; sadly, one of the patients died. Gene therapists had to assess the real risk-versus-benefit ratio for the use of retroviral vectors in patients and devise novel strategies to minimize the occurrence of insertional mutagenesis-related malignancies. In this respect, a particular emphasis was placed on the engineering of enhancer-less self-inactivating retroviridae-based systems.
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Generation of replication-competent RV in target cells or tissues is the primary risk related to the use of retroviral vectors.
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- Authors
- Romano, G., Matino, I. R., Pentimalli, F., Adamo, V., & Giordano, A.
- Affiliations
- Temple University (US)
- Thomas Jefferson University (US)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- University of Messina (IT)
- University of Siena (IT)
- Venue
- Drug News & Perspectives
- Publisher
- Portico
- Published
- 2009
- Volume
- 22
- Issue
- 4
- Pages
- 185
- ISSN
- 0214-0934 (ISSN-L)
- 2013-0139
- OpenAlex
- W2053474800
- Cited by
- 38
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 2 · 2014: 2 · 2013: 5 · 2012: 2
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug News & Perspectives (publishedVersion)
- PubMed (publishedVersion)
- Use Siena air (University of Siena) (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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- insertional mutagenesis, retroviral vectors, adeno-associated virus vectors, Sleeping Beauty transposon, phiC31 integrase, gene therapy safety, leukemia, X-linked severe combined immunodeficiency, vector integration, long-term transgene expression, risk-benefit assessment
- MeSH terms
- Animals, Clinical Trials as Topic, Genetic Vectors, Humans, Neoplasms, Genetic Therapy, Mutagenesis, Insertional, Gene Transfer Techniques
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