Abstract 
I . 
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. We propose in this 
protocol a phase I trial to assess the safety and feasibility of treating CF pulmonary disease by 
directly delivering CFTR-expressing, replication-defective 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, 10 CF patients will be treated with CFTR-expressing 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. 
II. Background 
II. A. Cystic Fibrosis 
Cystic fibrosis (CF) is the most lethal autosomal recessive disease in the Caucasian population 
[Boat et al., 1989]. The underlying pathology involves defects in anion transport across 
various epithelia. Approximately 1 in 2,500 live births are affected by this disease indicating 
that the carrier frequency is 1 in 25. Cystic fibrosis manifests itself in multiple organ 
systems including liver (focal biliary cirrhosis), intestines (bowel destruction), pancreas 
(malabsorption, pancreatitis, and diabetes), vas deferens (sterility in males) and lung 
(obstructive pulmonary disease and chronic infections). 
Although all mucus secreting organs of the body are affected in cystic fibrosis, it is the 
pulmonary disease that is responsible for the vast majority of the morbidity and mortality 
[Wood et al., 1976]. The age at onset of symptoms and the rate of progression of pulmonary 
disease can vary considerably from patient to patient. However, it is generally accepted that 
virtually every patient with cystic fibrosis who lives long enough will develop pulmonary 
complications from their disease. Recent progress in the areas of genetics and cell biology has 
done much to further our understanding of the pathogenesis of cystic fibrosis. Although a 
number of significant gaps still exist, the pathogenesis of the pulmonary disease is likely 
related to the recently described abnormalities in electrolyte transport within the airways. 
These abnormalities lead to production of an abnormal mucus with altered rheologic properties. 
This leads to impaired clearance of the bronchial lining fluid with resulting pooling of 
secretions within the airways. The stagnant secretions are suitable substrates for bacterial 
growth. For uncertain reasons, staphylococci and pseudomonas species are the most frequently 
cultured organisms found in the sputum of patients with cystic fibrosis. The repeated episodes 
of infection cause permanent airway damage of a type that leads to chronic obstruction in 
airflow and bronchiectasis. Symptomatically, the patient develops cough with sputum 
production and shortness of breath with exercise. As the disease advances, the level of dyspnea 
increases until it occurs at rest. With advanced disease, hypoxemia leading to cor pulmonale and 
right heart failure appear. Eventually ventilatory failure occurs followed by death. Data from 
1990 show that the median survival for cystic fibrosis in the United States is 27.6 years. 
Recombinant DNA Research, Volume 16 
[809] 
