There are several aspects of human brain tumor gene therapy, which are poorly understood and are currently difficult to assess in clinical trials. One of the key aspects relates to the efficacy of gene delivery and associated barriers while the another aspect relate to the efficacy of gene expression in vivo. The overall goal of this Project is to further develop and optimize imaging techniques that can ultimately be used to objectively monitor gene therapy. The imaging strategies utilized in this Project are based on previously developed novel techniques that allow and functional assessment during tumor growth, treatment and relapse.
The first aim quantitates delivery of MGH-1 vector to gliomas and other tissues using different delivery strategies. These studies are highly relevant since such quantitative data on viral gene delivery in vivo are currently lacking and may influence the design of future clinical trials.
The second aim will validate the in vivo use of previously developed marker genes (99m/Tc binding fusion proteins) to image gene expression. The fusion proteins are expressed on the cell surface of transduced cells, avidly transchelate oxotechnetate from weak chelator (e.g. glucoheptonate or glucarate) and unlike other """"""""receptor systems"""""""" have no biological function. The last aim of the Project will track genetically engineered cell based delivery vehicles developed in Project 4. Mass balances of administered cells and microscopic intratumoral distribution will allow us to monitor the distribution of injected cells. The proposed experiments will allow us to monitor the distribution of infected cells. The proposed experiments will utilize recently developed iron oxide nanoparticles coupled to membrane-traversing peptides (derived from HIV-tat protein) that allow detection of approximately 40 cells/voxel by NMR imaging using clinical imaging systems and single cells using experimental muNMR techniques. The current Project is highly unique in that these previously developed novel techniques and methods will now be applied to visualize vector distribution vector distribution and gene expression in gliomas. There is a high degree of interaction with other Projects and Cores (especially the Neuropathology and Pharmacology Core). The Project relies on the development of MGH-2 and novel cell vehicles and amplicons.
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