Gene therapy of cystic fibrosis lung disease using E1 deleted adenoviruses: a phase I trial.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by defective ion transport across various epithelia. Multiple organ systems are affected in this disease; however, the pulmonary complications are the most morbid and life limiting. The primary defect in the lung appears to be abnormal mucociliary clearance. Isolation of the gene responsible for CF in 1989 provided impetus for the development of new therapies based on gene therapy. W e propose in this protocol a phase I trial to assess the safety and feasibility of treating CF pulmonary disease by directiy delivering CFTR-expressing, replicationdefective adenoviruses to the airway. The rationale for this human protocol was based on extensive preclinical studies in a variety of animal models including human CF airway xenografts and nonhuman primates. In this protocol, 20 CF patients will be treated with CFTRexpressing virus and followed for a) evidence of CFTR gene transfer and expression, b) immunological responses to CFTR or adenoviral proteins, and c) toxicity. Adult CF patients with advanced disease who are considered acceptable candidates for bronchoscopy will be considered. A suspension of virus will be delivered to an isolated segment of the lung via a bronchoscope. Pulmonary samples will be harvested for analyses by follow-up bronchoscopies 4 days, 6 weeks, and 3 months following administration of the virus.