To realize the promise of non-viral gene therapy as a treatment modality for cancer, breakthrough technologies in several key steps have to be made, which includes 1) to develop a simplified but effective gene delivery system to increase the gene delivery efficiency;2) an effective gene expression system to extend the duration of therapeutic gene expression;3) develop a tumor-targeted gene to minimize the systemic toxicity;and 4) develop a novel strategy to overcome the resistance to the proposed therapeutic approach. The goal of this application aims to addresses the first two critical issues by exploring two innovative approaches. To address the delivery issues, the applicant will develop convection-enhanced delivery (CED)-combined with the electroporation delivery (EPD) system for gene delivery. The rationale is that CED increases the distribution of infused DNA in tumors and EPD will generate pores in cell membrane to allow DNA uptake. This novel strategy will increase the total number of cells to uptake DNA and increase the level of gene expression and therapeutic efficacy. To ensure that the proposed CED works on macromolecule plasmid DNA infusion, the applicant has innovated the conventional CED by proposing two modified strategies: a hydrodynamic CED and a needle array CED. Then, the applicant will develop an IFN-enhanced expression system, in which the IFN gene is driven by a CMV/IRF7 fusion promoter. The IFN product will activate the IRF7 promoter by feedback regulation to enhance the IFN gene expression and delay the termination of IFN gene expression. As a result, the gene expression duration will be extended. The applicant will combine the novel CED-EPD delivery system and the IFN-enhanced expression system to increase the therapeutic efficacy against tumors. Our hypothesis is that a high level accumulation of IFN in tumors will cause effective tumor regression. Our goal is to develop a simplified and effective non-viral gene therapy for treating tumors. The experiments that we propose have a high probability of success because we have an excellent model system in place, experience in the non-viral gene therapy field, and all the resources necessary to complete the task. The primary tumor model used for developing this therapeutic approach is squamous cell carcinoma that often occurs in oral cavity.
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