This is a single administration, multi-center, open label, dose escalation study designed to examine the safety of Targeted Genetics Corporation's recombinant adeno-associated virus with the cystic fibrosis transmembrane regulator gene (tgAAVCF), administered as an aerosol to patients with cystic fibrosis. Secondarily, samples will be obtained to evalate both delivery of the CFTR gene to the pulmonary epithelium, as measured by DNA PCR and expression of the CFTR gene, as measured by RT-PCR. Background: Cystic fibrosis (CF) is the most common autosomoal recessive disease, affecting between 1 in 2,000 and 1 in 4,500 children of Caucasion origin. The main characteristics are malabsorption due to exocrine pancreatic insufficiency, recurrent bacterial infections of the lower respiratory tract, abnormal regulation of salt transport across the gastrointestinal and respiratory epithelium, and male infertility due to absence or stenosis of the vas deferens. Early in the disease, the airways become filled wtih thick purulent mucus. There is chronic bacterial colonization of the airway epithelium, particularly with Pseudomonas aeruginosa, and intense neutrophil infammation. Over time, injury to the airwayss caused by inflammation results in bronchiectasis, parenchymal scarring and destruction, and consequent progressive respiratory failure. The gene involved in CF, the cystic fibrosis transmembrane conductance regulator (CFTR) gene was discovered in 1989. Gene therapy holds the promise of addressing the primary defect in CF by reconstituting proper chloride transport in vivo. For treatment of lung disease in patients with CF, a vector will most likely have to be administered as an aerosol. An ongoing clinical trial of bronchoscopic administration of tgAAVCF to the right lower lobe of the lung suggests that tgAAVCF is safe for pulmonary delivery. Thus, the current protocol will test the delivery of aerosolized tgAAVCF in a dose escalation clinical trial.
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