Development of a Generic Pharmacodynamic Reporter Model for Assessing in vivo Activity and Selectivity of Targeted siRNA

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Short interfering RNAs (siRNAs) can reduce the expression of disease-related genes by binding to and mediating the degradation of mRNA (the intermediate of DNA and protein) to which they are complementary. However therapeutic siRNA must be delivered to appropriate parts of the body which is a significant challenge. If the organs are not directly accessible i.e. skin, eyes, muscles, then siRNA must be delivered via the blood stream. Currently there are no methods to sensitively determine both the quantity and efficacy of siRNA reaching the desired organ in a living animal. We propose to create a mouse that will express light (detected by a camera) in organs where siRNA has been delivered. Mouse models will be created by introducing two pieces of foreign DNA into every cell in the mouse, one that makes light emitting protein and one that makes a repressor protein that regulates light expression. When siRNA that specifically recognises the repressor mRNA enters cells the amount of repressor protein will fall and light will be generated. By combining target specificity and biological functionality this model will permit testing of various siRNA delivery mechanisms leading to improved design and effectiveness.