It is essential to monitor transgene expression for efficacy and safety of human gene therapy. Use of a reporter gene to monitor gene delivery and expression in targeted tissue represents an innovative molecular imaging technique. After simultaneous delivery of a reporter gene with a therapeutic gene, imaging signals from a reporter gene indirectly reflect the distribution and expression of a therapeutic gene in vivo. Because there are some limitations associated with the reporter genes currently available, it is necessary to search for new reporter genes which may be used when use of other reporter genes is limited. Human copper transporter 1 (hCtrl) gene encodes a high affinity copper transporter. Endogenous hCtrl is highly expressed in liver, with much lower expression in extra-hepatic tissues. Here, we hypothesize that hCtrl may be used as a reporter gene for imaging gene delivery in vivo by PET. We will perform exploratory experiments with two specific aims.
AIM 1 : To determine whether over-expression of hCtrl in tumor tissue can be imaged non-invasively and quantitatively by Cu-64 PET, using human cervical carcinoma xenograft in mice as an experimental animal model.
AIM 2 : To evaluate feasibility using hCtrl as a reporter gene for imaging transcriptional targeting of hCtrl expression to tumor over-expressing N-MYC oncoprotein by Cu-64 PET, using human neuroblastoma xenograft in mice as an animal model. This new reporter gene may have unique desirable features in comparison to other reporter genes: 1) hCtrl will not stimulate immunological reaction in humans and is expected to be very useful for longitudinal monitoring of transgene expression non-invasively and quantitatively; 2) the hCtrl reporter gene is expected to be especially useful for imaging targeted gene delivery in prostate cancer gene therapy because there is little background activity in the urinary bladder; 3) hCtrl holds potential as a therapeutic gene based on its capability to medicate cellular uptake of cisplatin. The data from this pilot study will help us to determine whether it is feasible to use hCtrl as a reporter gene for imaging. Successful development of this new hCtrl reporter gene is expected to contribute to advance of human gene therapy significantly by providing a versatile reporter gene for longitudinal monitor of transgene expression in vivo non-invasively and qunatitatively by PET imaging. ? ? ? ?
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