Cystic fibrosis (CF) is the most common fatal genetic disorder in the United States. Fewer than 50% of CF patients survive to age 31. The disease is characterized by impaired ion transport in epithelial-lined organs, especially the lungs. CF pathology results from defects in the cystic fibrosis transmembrane conductance regulator (CFTR). The defects impair chloride transport, and indirectly impair sodium transport by the epithelial sodium channel (ENaC). The combined impaired ion transport results in increased viscosity of the mucous lining the pulmonary airways. This results in blocked airways and a high susceptibility to pulmonary infection, and ultimately pulmonary failure and death. Inhibition of the ENaC is effective in reducing mucous viscosity and consequently CF pathology.
Aims 1 through 3 propose to identify optimal antisense inhibitors of the ENaC mRNA. Subsequently, these results will be used in phase two of the project to develop potent antisense therapeutics for the treatment of CF.
The aims of the proposal are 1) produce antisense RNA and ribozyme libraries targeting the human epithelial sodium channel; 2) use the RNA and ribozyme libraries to identify effective anti-ENaC antisense RNAs and ribozymes; 3) verify the activity of the identified antisense molecules.