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Coexpression of Herpesviral Thymidine Kinase Reporter Gene and VEGF Gene for Noninvasive Monitoring of Therapeutic Gene Transfer: An In Vitro Evaluation

¹ Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Munich, Germany
² Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Munich, Germany
³ Institute of Bioinorganic and Radiopharmaceutical Chemistry, Forschungszentrum Rossendorf, Germany
⁴ Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York

Coexpression of a reporter gene and a therapeutic gene may allow for noninvasive monitoring of cardiac gene therapy. We sought to evaluate the usefulness of an adenoviral vector expressing mutant herpesviral thymidine kinase reporter gene (HSV1-sr39tk) and vascular endothelial growth factor (VEGF) 121 in independent expression cassettes (Ad4tk). Methods: Accumulation of ¹⁴C-2'-fluoro-5-methyl-1-ß-D-arabinofuranosyluracil (FIAU) and 9-(4-¹⁸F-fluoro-3-hydroxymethylbutyl)guanine (FHBG) as reporter probes, and secretion of VEGF into medium, were determined for Ad4tk-infected H9c2 rat cardiac cells in vitro. Results: In vitro tracer uptake increased with increasing vector concentration and over time. It was comparable to cells infected with adenovirus expressing only wild-type HSV1-tk (reporter probe: ¹⁴C-FIAU) or mutant HSV1-sr39tk (reporter probe: ¹⁸F-FHBG). No significant uptake was observed in cells infected with adenovirus expressing VEGF alone. With increasing vector concentration, Ad4tk-infected cells increasingly released VEGF into medium. VEGF production correlated significantly with cellular reporter probe uptake (r = 0.93; P = 0.0003). Conclusion: The usefulness of a vector coexpressing HSV1-tk and VEGF for noninvasive imaging of expression of a therapeutic transgene has been demonstrated in vitro. This approach may allow for future in vivo monitoring of cardiac angiogenesis gene therapy.

Key Words: gene therapy • reporter genes • VEGF • HSV1-tk • heart

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