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Comparison of toxicogenomic profiles of two murine strains treated with HIV-1-based vectors for gene therapy.

Zhao Y, Keating K, Thorpe R

Biotherapeutics Group, National Institute for Biological Standards and Control, Blanche Lane, Potters Bar, Hertfordshire, EN6 3QG, UK. yzhao@nibsc.ac.uk

Gene therapy vectors based on lentiviruses persist in the host and are ideally suited for long-term therapies of genetic disorders. However, recent incidences of T cell leukemia in X-SCID children receiving gene therapy reveal discrepancy among the preclinical and clinical studies. Divergent results on the potential oncogenic property of integrating vectors obtained from different animal models further raise concern about the relevance and sensitivity of available preclinical systems used to assess their toxicity. Evaluation of transcriptional responses to vector transduction in different in vivo models may provide us with early indications of the potential adverse effects of these vectors and comparative information on the sensitivity and suitability of these models. For this purpose, we used cDNA microarray to examine transcriptional changes in BALB/c and CD-1 (IRC) mice, the two common murine strains used in pharmacological and toxicological studies. Our results revealed a significant difference in the transcriptional responses to vector transduction between the two mouse strains. Modest gene changes, in terms of gene numbers and gene expression were observed in BALB/c mice, whereby expression of 15 oncogenes was up-regulated in CD-1 (ICR) mice. We confirmed the up-regulation of oncogenes, e.g., N-myc, A-Raf, Fli-1, Wnt-2b, and c-jun in CD-1 (IRC) mice using RT-PCR. This study provided an insight into the function of lentiviral transduction in different mouse strains. Distinctive toxicogenomic profiles of two mouse strains should be considered in the context of future development of sensitive models for toxicity evaluation of lentiviral vector products.

Published 20 November 2007 in Toxicol Appl Pharmacol, 225(2): 189-97.
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