ADENOVIRUS MEDIATED GENE TRANSFER FOR CYSTIC FIBROSIS

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The primary objective of this study is to evaluate the safety and biochemical efficacy of single escalating doses of Ad2/CFTR-2 aerosolized to thelungs of cystic fibrosis patients. To achieve this objective while assessing and mimizing potential risks associated with delivery of Ad2/CFTR-2 to the lower airways, single escalating doses of Ad2/CFR-2 will be delivered (through a bronchoscope) to a single lobe of the lung of cystic fibrosis patients prior to aerosolizing the same dose to the lung. Cystic Fibrosis (CF), is a lethal autosomal recessive disease which affects between 25,000 and 30,000 Americans. Some symptoms of the disease include chronic bronchitis and pneumonia, obstructive lung diseae, pancreatic insufficiency, failure to thrive, diabetes, cirrhosis, intermittent hyponatremic dehydration, azospermia, and sinusitis. Currently nonspecific therapy has improved morbidity, but 50% patietn survival is only 30 years. The disease results from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a protein which forms a chloride channel that is regulated by phosphorylation and by intra-cellular nucleotides. Mutations in the CFTR gene cause a loss of CFTR chloride channel activity and thus contribute to the hallmark physiology of the disease: defective electrolyte transport by affected apithelia. Our current understanding of the structure and function of CFTR suggests that gene transfer could represent an important advance in treatment. The demonstration of in vitro correction of the gene defect established thefeasibility of in vivo correction with the appropriate vector-delivery system. In this study, the investigators are assessing the safety and biochemical efficacy of single escalating doses of Ad2/CFTR-2 delivered to the lower airway. Delivery will move from direct, lobar, bronchoscopic administration to a whole lung, aerosol method during the course of the investigation. This is currently the only approved aerosol gene therapy protocol for CF in North America. Successful demonstration of effect in a safe manner should allow follow up studies on repetitive dosing in an efficacy trial.