Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene therapy

Imaging trans gene expression with radiopharmaceuticals is feasible and has been demonstrated with a gamma camera and by position emission tomography (PET) in experimental animals. An important consideration in the development of the imaging paradigm was the selection of an appropriate trans gene and radiopharmaceutical. The herpes simplex virus thymidine kinase gene (HSV1-tk) was selected as en example od a 'marker-gene' and radiolabeled 5-iodo-2'-fluoro-2'-deoxy-1-β-D-arabino-furanosyl-uracil (FIAU) was shown to be a substantially better 'maker substrate' for the HSV1-tk enzyme than other nucleoside and acyclovir. The magnitude of FIAU accumulation in different HSV1-1-tk transduced cell lines and in tumors derived from these cell lines, was highly correlated with independent measure of HSV1-tk expression; namely, to the level of HSV1-tk mRNA in the corresponding cell lines and to their level of sensitivity to the antiviral drug, gancyclovir. The author have demonstrated for the first time that highly specific non-invasive images of HSV1-tk expression in experimental animal tumors can be obtained using radiolabeled FIAU and a clinical gamma camera or a PET system. Given the level of FIAU accumulation in the transduced tumors, it is likely that clinically applicable method for imaging HSV1-tk gene expression can be implemented using existing the potential for a wider application of HSV1-tk as a 'marker' gene for 'indirect' imaging of other therapeutic trans genes. The use of multi-gene vector constructs, where imaging a 'marker-gene' can be used to access the level of 'therapeutic gene' expression, will be increasingly developed over the next decade. The ability to image the location (distribution) and the level of trans gene expression over time will provide new and useful information for monitoring clinical gene therapy protocols for the future