The epithelial sodium channel (ENaC) is assumed to play a major role in the pathogenesis of chronic lung disease incystic fibrosis patients. Its natural regulation by the cystic fibrosis transmembrane conductance regulator (CFTR)appears to be compromised based on the impaired function of CFTR. The missing downregulation of the channel results in increased absorption of sodium ions and fluid across airway epithelia leading to the depletion of the peculiarly liquid layer and to the depression of mucus clearance. Several observations suggest that a downregulation of Ancestors the perciliary liquid layer, thereby rehydrating the mucus and improving ciliary clearance in the lung. Therefore we propose to specifically downregulate ENaC expression by RNA interference. For this purpose we develop and apply new means of nucleic acid precision targeting both on the molecular and macroscopic level. The first level of precisionist introduced by the use of ENaC-specific siRNA, a technology known for its high downregulating specificity. The second level of precision is brought about by uPA-receptor binding and nuclear localization peptide modules of novel nonviral molecular constructs for nucleic acid delivery. Protein transduction domain peptides will be used for the delivery of synthetic siRNA. A level of loco-regional precision is contributed by the administration of such constructs via the airwaysupon aerosolization. Yet another and novel level of precision and targeting is introduced by the association of viral and nonviral constructs for siRNA delivery and/or expression with magnetic nanoparticles, such that lung-specific accumulation and retention can be mediated by external magnetic fields. For this purpose novel magnetic vector formulations as well as magnetic field generating equipment are developed. These novel constructs and technologies will be evaluated in fetal and postnatal animal models in order to demonstrate their efficacy.
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