Cystic Fibrosis (CF) has been at the forefront of gene transfer research for the last decade. This disease, resulting from a single gene defect, affects the epithelia of multiple organs of the body including the lung and gastrointestinal tract. The lack of effective long-term treatment for the pulmonary manifestations of CF, the accessibility of the lung via the airway lumen, and the fact that viruses known to infect the lung were being developed into non-replicating gene transfer vectors led investigators to believe that administration of gene transfer vectors to the lung could potentially result in an effective treatment of this disease. The assessment of the efficacy of gene transfer for CF requires a routine and reliable assay to verify expression of functional CFTR. This Correction Core will provide multiple techniques to detect the efficacy of CFTR gene transfer at correcting the ion, fluid and mucus transport defects in both the airway and gut. Cultured airway epithelia from the CF human and mouse will be used extensively in Ussing chamber studies to demonstrate correction of the CFTR mediated Cl- secretion and Na+ hyperabsorption. These preparations will also be used to determine if the altered rate of fluid transport has been corrected by CFTR gene transfer using confocal microscopy and measurement of blue dextran absorption. The pH and mucus biophysical properties will be measured on CF cultured airway epithelia to ascertain CFTR correction. Both human and murine nasal PD assays will be provided to assess CFTR gene transfer in vivo. Ion transport across CF human rectal biopsy studied in Ussing chambers will also be available as will freshly excised epithelial tissue from neonatal murine airways and gut to measure the effectiveness of in vivo vector dosing in neonatal CF mice. Finally, in anticipation of a new animal model for CF (a CF pig) we have begun to characterize the bioelectric properties of the porcine epithelium so that we will be poised for those possible studies.
CF is the most common fatal genetic disorder of the Caucasian population. Gene transfer approaches provide one of the best possibilities to cure this disease. The novel techniques described in this proposal will provide gene transfer investigators routine access to high-quality, high-sensitivity, well-controlled, robust measures of CFTR correction.
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