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Cited by 42Virus-based gene therapy researchCAR-T cell therapy researchCRISPR and Genetic Engineering

Evaluating the Safety of Retroviral Vectors Based on Insertional Oncogene Activation and Blocked Differentiation in Cultured Thymocytes

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Zhou, Sheng, Fatima, Soghra, Ma, Zhijun, Wang, Yong-Dong, Lu, Taihe, Janke, Laura J, Du, Yang, Sorrentino, Brian P·2016·Molecular Therapy
DOI 10.1038/mt.2016.55PMC PMC4923324
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Abstract

Insertional oncogenesis due to retroviral (RV) vector integration has caused recurrent leukemia in multiple gene therapy trials, predominantly due to vector integration effects at the LMO2 locus. While currently available preclinical safety models have been used for evaluating vector safety, none have predicted or reproduced the recurrent LMO2 integrations seen in previous X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich clinical gene therapy trials. We now describe a new assay for assessing vector safety that recapitulates naturally occurring insertions into Lmo2 and other T-cell proto-oncogenes leading to a preleukemic developmental arrest in primary murine thymocytes cultured in vitro. This assay was used to compare the relative oncogenic potential of a variety of gamma-RV and lentiviral vectors and to assess the risk conferred by various transcriptional elements contained in these genomes. Gamma-RV vectors that contained full viral long-terminal repeats were most prone to causing double negative 2 (DN2) arrest and led to repeated cases of Lmo2 pathway activation, while lentiviral vectors containing these same elements were significantly less prone to activate proto-oncogenes or cause DN2 arrest. This work provides a new preclinical assay that is especially relevant for assessing safety in SCID disorders and provides a new tool for designing safer RV vectors.

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  • An assay developed to test the oncogenic potential of gammaretroviral and lentiviral vectors may further improve safety when designing vectors for clinical use.

    “An assay developed to test the oncogenic potential of gammaretroviral and lentiviral vectors may further improve safety when designing vectors for clinical use [60].”

    From Clinical use of lentiviral vectors (2018) · cites this paper as [60]

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Research works printed but not linked: 45

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Authors
Zhou, S., Fatima, S., Ma, Z., Wang, Y.-D., Lu, T., Janke, L. J., Du, Y., & Sorrentino, B. P.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Uniformed Services University of the Health Sciences (US)
Corresponding author
Sorrentino, Brian P
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2016-06
Volume
24
Issue
6
Pages
1090-1099
ISSN
1525-0016 (ISSN-L)
DOI
10.1038/mt.2016.55
PMC
PMC4923324
OpenAlex
W2293164235
Cited by
42
References
51
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (P01HL053749)
  • National Cancer Institute (P30CA021765)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
retroviral vectors, vector safety, insertional oncogenesis, LMO2, thymocytes, long terminal repeat, lentiviral vectors, gammaretroviral vectors, X-linked severe combined immunodeficiency, Wiskott-Aldrich syndrome
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Genetic Vectors, Humans, Up-Regulation, Lentivirus, Mutagenesis, Insertional, Gammaretrovirus, Adaptor Proteins, Signal Transducing, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Thymocytes, LIM Domain Proteins, MEF2 Transcription Factors

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