Assessment of Gene Transfer Using Imaging Methodology

Annette      Altmann; Uwe      Haberkorn

Abstract

Targeting of the therapeutic genes to the malignant or non-malignant tissue may be achieved using recombinant viral vectors for the transfer and tissue-specific or tumor-specific regulatory sequences. However, the efficiency of the recombinant viruses to infect tumor cells, was shown to be rather low. Therefore, repeated injections of the virus might be required to obtain a sufficient therapeutic response and in clinical trials non-invasive procedures have to be employed to assess the transfer and functional activity of the recombinant gene. In gene therapy based on the transfer and expression of the suicide genes usually genes coding for the non-mammalian enzymes, the Herpes simplex virus thymidine kinase (HSVtk) or the yeast and bacterial cytosine deaminase (CD), have been applied. After infection of the tumor with the recombinant virus, the non-toxic prodrug is applied systemically, which is subsequently converted to a toxic metabolite by the recombinant gene product. Employing a radiolabeled prodrug and scintigraphic procedures to determine the functional activity of the recombinant enzyme in vivo, a therapeutic window of maximal gene expression and consecutive drug administration may be defined. If the gene therapy approach is based on the transduction of receptor genes, the recombinant gene expression in tumor cells will be monitored using radiolabeled ligands. Transfer of transporter genes as the sodium iodide transporter may also lead to the visualization of transduction via accumulation of iodide or pertechnetate. Furthermore, imaging based on transchelation of oxotechnetate to a polypeptide motif from a biocompatible complex with a higher dissociation constant than that of a dicglycilcysteine complex or tyrosinase gene transfer for metal ion scavenging have been described. In addition, the monitoring of the gene therapy effects is performed by the evaluation of the morphological changes of the tumor using magnetic resonance imaging or, more effectively, by the measurement of the tumor-associated metabolic variations with positron emission tomography (PET) employing tracers of tumor metabolism and proliferation. The uptake of 18Fluordeoxyglucose (FDG) has been demonstrated to be a useful parameter for the assessment of the glucose metabolism and the tumor growth may be elevated by the uptake of (11C)thymidine or other proliferative markers.

Keywords: gene transfer, imaging methodology, pet, positron emission tomography

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