Cystic fibrosis (CF) is an autosomal recessive disorder resulting from abnormal functional expression of the CF gene product, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is an integral membrane protein that targets to the apical surface of epithelial cells and functions as a chloride channel. Epithelial cells in a number or organs are affected by mutations in CFTR. However, loss of CFTR function in respiratory epithelium leads to the most devastating complication of the disease, repeated pulmonary infection and progressive lung destruction. The full spectrum of activities of CFTR within the respiratory tract appears to extend beyond its function as a gated chloride channel. Recent studies have indicated that the CF airway is not only characterized by alterations in sodium and chloride transport but also by changes in mucin composition, inflammatory cells and mediators, and anitmicrobial peptide function. Thus it appears unlikely that one pharmocologic agent would be able to restore the multiple regulatory functions attributable to CFTR. One attractive strategy to restore the multiple functional properties of CFTR in CF lungs is to deliver wild type human CFTR to the respiratory epithelium using one of a number of gene delivery techniques. Based on extensive pre-clinical testing and previous clinical studies, it was determined that first and second generation adenovirus vectors may have limitations with regards to transient gene expression due to vector stimulation of an inflammatory response. Therefore, it was hypothesized that the use of a third generation adenoviral vector would enhance transgene expression by reducing the host inflammatory response to vector administration. A phase I study was conducted using the third generation adenoviral vector expressing the CFTR gene. Vector suspension was administered via bronchoscope into a lobar segment in a total of 11 patients. The results of this study are presented in the publication cited above. Dose limiting toxicity appeared to be reached at a dose of 2.1 x 109 pfu based on the development of flu-like symptoms and transient fluffy diffuse infiltrates on chest x-ray.
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