This application describes an alternative to better targeting which is achieved by delivery of inactive genetic material non-specifically followed by local activation with light. This proposal is based on novel strategy to temporarily alter plasmid DNA to block transcription. An important feature of this inactivation strategy is that restoration of transcription after transcellular delivery can be achieved by localized light to the targeted skin region. Targeted delivery of therapeutic genetic material to the endothelium of the skin is difficult, particularly for non-viral delivery methodologies. In general, the targeting problem has been viewed as dependent on two critical steps: (1) delivery of the gene to the target cell population and (2) its subsequent expression. Hypothesizing that increasing the efficiency of targeted delivery will overcome apparently low expression rates, a number of laboratories have sought to improve nonverbal methods by focusing on the first step and hence seek to enhance the specificity of delivery vehicles for target cells. We propose to test this novel targeting strategy which may be particularly useful in some skin diseases in which altered endothelial function might block or reverse the progression of disease.
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