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Basic Science Investigations |
1 Department of Nuclear Medicine, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea
2 Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
The sodium/iodide symporter (NIS) gene allows convenient reporter imaging with 
-cameras and free radioiodide. In this study, we investigated the accuracy of this technique for assessing myocardial gene expression in living rats by using a dual-gene adenovirus that expresses both NIS protein and enhanced green fluorescent protein (EGFP). Methods: Rats underwent myocardial injection with the dual-gene adenovirus (Ad.EGFP.NIS) or a control virus (Ad.EGFP). 123I scintigraphy was performed at day 4, and ratios of cardiac counts to mediastinal count were measured. The site of radiouptake was localized by use of dual-isotope 201Tl images, and radioiodide efflux rates were evaluated by dynamic imaging. The dependence of cardiac radiouptake on viral titers and the sensitivity of detection of cardiac radiouptake were investigated at various viral titers. The radioactivity, EGFP, and NIS protein expression sites were compared microscopically. The correlation of image-based uptake with fluorometric measurements of EGFP concentrations was assessed by regression analysis. Results: 123I scintigraphy demonstrated clear focal myocardial uptake at the Ad.EGFP.NIS injection site, with relatively slow washout rates (3.3% ± 0.8%/h), despite the absence of organification. Image-based cardiac uptake increased in a viral titer–dependent manner, with a detection threshold of between 3 x 106 and 1 x 107 plaque-forming units. Western blotting showed titer-dependent increases in myocardial NIS protein expression. Tissue radioactivity levels approached 12.5-fold control levels and correlated closely with image-based uptake (r = 0.91; P < 0.0001). Histologic analysis confirmed the colocalization of radiouptake, EGFP fluorescence, and NIS staining. Image-based uptake showed a strong correlation with fluorometric measurements of myocardial EGFP concentrations (r = 0.81; P < 0.0001). Conclusion: Our results demonstrate that convenient myocardial gene imaging with -cameras and radioiodide is feasible with the NIS gene. Moreover, the use of this technique with a dual-gene vector appears to allow accurate assessment of the level of myocardial expression of a second gene of interest.
Key Words: reporter gene • gene therapy • myocardium • radioiodide • scintigraphy
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