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 pulmopnary complications are the most morbid and life limiting. The primary defect in the lung appears to be abnormal mucociliary clearance. Isolatin of the gene responsible for CF in 1989 provide impetus for the development of new therapies based on gene therapy. The most promising technology for developing gene therapy for CF is based on recombinant adenoviruses. Based on extensive-preclinical testing, a phase I trial was initiated to evaluate the safety and biological efficacy of first generation recombinant adenoviruses expressing the CF gene product, the CF transmembrant conductance regulator (CFTR). The original goal was to define a therapeutic index for intrapulmonary administration of recombinant adenovirus. Each patient was instilled with a solution of adenovirus into a pulmonary segment via a bronchoscope. Toxicity and biological efficacy (i.e. efficiency and stability of gene transfer) were evaluated. Ten study groups (2 patients/group) were approved with each group receiving an incremental increase in virus dose. This trial proceeded through the first eight patients representing the initial four treatment groups. There was no toxicity referable to gene therapy nor was there consistent demonstration of gene transfer. After the initiation of our clinical trial, we continued to expand studies in pre-clinical models. These additional animal experiments suggested that first second generation adenoviruses may have limitations that lead to transient expression of recombinant CFTR and the development of inflammation. A third generation virus was further crippled to partially circumvent these potential problems. We then amended our protocol and began another phase I trial using the improved recombinant CFTR virus. A total of 14 patients have been/will be enrolled in the study with the initial dose starting at the last previous dosage group of the initial study (i.e., 2.1 x 107 total pfu dose). Virus has been/will be administered to the lung via a bronchoscope. Pulmonary samples have been/will be harvested for analysis by follow-up bronchoscopies 4 and 42 days following administration virus.
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