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

Sheng Zhou1, Soghra Fatima1, Zhijun Ma1

  • 1Division of Experimental Hematology, Department of Hematology, Memphis, Tennessee, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|March 10, 2016
PubMed

Insights

New gene therapy safety models reveal retroviral vector risks. Gamma-retroviral vectors carrying LMO2 integrations cause leukemia, while lentiviral vectors show improved safety profiles for treating severe combined immunodeficiency (SCID).

Area of Science:

  • * Molecular Biology
  • * Immunology
  • * Oncology

Background:

  • * Retroviral (RV) vector integration into proto-oncogenes like LMO2 has led to leukemia in gene therapy trials.
  • * Current preclinical models fail to predict or replicate LMO2 integrations observed in X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich trials.
  • * Developing accurate safety models is crucial for advancing gene therapy, particularly for immune deficiencies.

Purpose of the Study:

  • * To develop and validate a novel preclinical assay for assessing retroviral vector safety.
  • * To compare the oncogenic potential of gamma-retroviral (RV) and lentiviral vectors.
  • * To evaluate the impact of different transcriptional elements on vector-induced oncogenesis.

Main Methods:

  • * A new in vitro assay using primary murine thymocytes to model insertional oncogenesis.
  • * Assessment of vector integration into Lmo2 and other T-cell proto-oncogenes.
  • * Comparison of gamma-RV and lentiviral vectors with varying transcriptional elements, including long terminal repeats (LTRs).

Main Results:

  • * The novel assay recapitulated Lmo2 integrations and induced a preleukemic developmental arrest (DN2 arrest) in murine thymocytes.
  • * Gamma-RV vectors with full LTRs were most oncogenic, frequently activating the Lmo2 pathway and causing DN2 arrest.
  • * Lentiviral vectors with identical elements demonstrated significantly lower proto-oncogene activation and DN2 arrest rates.

Conclusions:

  • * A new preclinical assay accurately models retroviral vector-induced oncogenesis, particularly LMO2 pathway activation.
  • * Gamma-RV vectors pose a higher risk for insertional oncogenesis compared to lentiviral vectors.
  • * This assay is vital for evaluating gene therapy safety in SCID disorders and designing safer retroviral vectors.

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