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Cited by 114Virus-based gene therapy researchCRISPR and Genetic EngineeringCAR-T cell therapy research

Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity

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Wu, Chuanfeng, Dunbar, Cynthia E.·2011·Frontiers of Medicine
DOI 10.1007/s11684-011-0159-1PMC PMC3508510
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Abstract

Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.

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  • Clinical data suggest that the only cases of insertional mutagenesis were reported in genetically modified proliferative HSCs rather than quiescent cell types.

    “This is suggested by clinical data in which the only cases of insertional mutagenesis were reported in genetically modified proliferative HSCs rather than quiescent cell types [48].”

    From Clinical use of lentiviral vectors (2018) · cites this paper as [48]

    The SCID-X1 clinical-trials section reports leukemias after patients received genetically modified CD34+ stem cells. The ‘Impact of target cell characteristics’ section says malignant transformation was not observed in trials modifying mature T cells. It does not establish that all reported insertional-mutagenesis cases occurred in proliferative HSCs rather than quiescent cell types; its clinical comparison concerns malignant transformation, not every insertional event. Our copy provides no page numbers for these passages. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Wu, C., & Dunbar, C. E.
Affiliations
National Institutes of Health (US)
Corresponding author
Wu, Chuanfeng
ORCID
Venue
Frontiers of Medicine
Publisher
Springer Science and Business Media LLC
Published
2011-12
Volume
5
Issue
4
Pages
356-371
ISSN
  • 1673-7342 (ISSN-L)
  • 2095-0217
  • 2095-0225
DOI
10.1007/s11684-011-0159-1
PMC
PMC3508510
OpenAlex
W1978290943
Cited by
114
References
7
Citations by year
2026: 4 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 8 · 2017: 4 · 2016: 8 · 2015: 6 · 2014: 12 · 2013: 10 · 2012: 8
FWCI
1.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Frontiers of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (Z99 HL999999)
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
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Keywords
hematopoietic stem cell gene therapy, insertional mutagenesis, genotoxicity, proviral integration, leukemia risk, clonal expansion, proto-oncogene activation, genotoxicity testing, gene therapy safety, X-linked severe combined immunodeficiency, adenosine deaminase deficiency, adrenoleukodystrophy, thalassemia, chronic granulomatous disease, Wiskott-Aldrich syndrome
MeSH terms
Genetic Vectors, Hematopoietic Stem Cells, Humans, Genetic Therapy, Mutagenesis, Insertional, Induced Pluripotent Stem Cells

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