Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials

Elke Will, Jeff Bailey, Todd Schuesler, Ute Modlich, Brenden Balcik, Ben Burzynski, David Witte, Gerlinde Layh-Schmitt, Cornelia Rudolph, Brigitte Schlegelberger, Christof von Kalle, Christopher Baum, Brian P. Sorrentino, Lars M. Wagner, Patrick Kelly, Lilith Reeves, David A. Williams

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Although retroviral vectors are one of the most widely used vehicles for gene transfer, there is no uniformly accepted pre-clinical model defined to assess their safety, in particular their risk related to insertional mutagenesis. In the murine pre-clinical study presented here, 40 test and 10 control mice were transplanted with ex vivo manipulated bone marrow cells to assess the long-term effects of the transduction of hematopoietic cells with the retroviral vector MSCV-MGMTP140K wc. Test mice had significant gene marking 8-12 months post-transplantation with an average of 0.93 vector copies per cell and 41.5% of peripheral blood cells expressing the transgene MGMTP140K, thus confirming persistent vector expression. Unexpectedly, six test mice developed malignant lymphoma. No vector was detected in the tumor cells of five animals with malignancies, indicating that the malignancies were not caused by insertional mutagenesis or MGMTP140K expression. Mice from a concurrent study with a different transgene also revealed additional cases of vector-negative lymphomas of host origin. We conclude that the background tumor formation in this mouse model complicates safety determination of retroviral vectors and propose an improved study design that we predict will increase the relevance and accuracy of interpretation of pre-clinical mouse studies.

Original languageEnglish (US)
Pages (from-to)782-791
Number of pages10
JournalMolecular Therapy
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Will, E., Bailey, J., Schuesler, T., Modlich, U., Balcik, B., Burzynski, B., Witte, D., Layh-Schmitt, G., Rudolph, C., Schlegelberger, B., von Kalle, C., Baum, C., Sorrentino, B. P., Wagner, L. M., Kelly, P., Reeves, L., & Williams, D. A. (2007). Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials. Molecular Therapy, 15(4), 782-791. https://doi.org/10.1038/sj.mt.6300083