The use of the plasmid DNA for gene thearpy offers several advantages including safety and simplicity but is also hindered by relatively low levels and short durations of gene expression. Co-administration of nonionic poly (ethylen oxide)-poly (propylene oxide) block copolymers (Pluronic) has greatly increased the trangene expression of the plasmid DNA in the muscle. These block coplymers were shown to be safe in human clinical trials for cancer chemotheray, which supports their evaluation for possible use in gene therapy. The objectives of the proposal are 1) to determine the most efficient Pluronic compositions for plasmid DNA delivery in the muscle, 2) to determine the mechanism by which Pluronic enhances transgene expression, and 3) to evaluate this system for delivery of DNA vaccines targeting malignant melanoma. The proposed studies will (1) determine the optimal formulation of Pluronic and plasmid DNA to achieve high levels of transgene expression after administration in skeletal muscle in a mouse; (2) determine how Pluronic affects uptake, transcription and translation of the transgene in the muscle; (3) determine whether Pluronic induces trancriptional activation of transgene expression by activating signal transduction pathways; (4) evaluate Pluronic-formulated DNA vaccines expressing melanoma differentiation antigens and GM-CSF as an immune adjuvant in a mouse melanoma model. These studies will be conducted in collaboration with a co- investigator at Memorial Sloan Kettering Cancer Center who has expertise in pre-clinical and clinical DNA immunizations against malignant melanoma. ? ? ? ?
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