cells to permit expression of normal CFTR mRNA transcripts and CFTR protein; 2) 
whether there is a local inflammatory response or the development of a systemic 
inflammatory response; 3) whether it corrects the abnormal ion transport phenotype 
seen in CF (i.e., raised nasal potential difference and the inability to secrete Cl" in 
response to cAMP-mediated agonists); and 4) the duration of both responses. 
VA.2. Rationale 
The nasal epithelium shares the ion transport abnormalities of the 
tracheobronchial epithelium in CF and demonstrates similar morphology and cell 
function as lower airway epithelium. We have performed extensive in vivo studies of 
ion transport in both nasal and lower respiratory epithelium of CF and normal 
subjects and used pharmacologic perturbation to explore the nature of the genetic 
defect in CF. In addition, the nasal epithelium is a site relatively free of bacterial 
infection, and is relatively accessible for administration of the recombinant 
adenoviral vector and for sampling epithelium for studies of inflammation and 
expression of mRNA and protein. It is also accessible for performing studies of 
biological efficacy [potential difference (PD)] measurements. 
V.B. Patient selection 
The initial study will be composed of 9 CF patients; each of three escalating 
doses of CFTR will be administered to three patients. 
Inclusion criteria 
1. Patients with the diagnosis of CF based on characteristic clinical disease 
and a sweat Cl" test of > 60 mEq/L. 
2. Mild to moderate disease, i.e., FEVi >40% predicted, (or FEVi J>1 L), 
and stable pulmonary disease, i.e., no pulmonary exacerbations within the past 3 
weeks. 
3. Male and/or female subjects j> age 18 years. 
4. Genotype: The "gold standard" would be homozygous AF508 patients. 
However, gene heterozygotes for AF508 are eligible if the patient has pancreatic 
insufficiency, i.e., does not have a mild mutation on the other allele, as are patients 
who have no AF508 mutation if their clinical disease is compatible with having two 
"severe" mutations, i.e., pancreatic exocrine insufficiency. 
5. Seropositivity for antibody to adenovirus type 5. Seropositivity is very 
common (>70%) in the general population, and systemic immunity likely is 
desirable in this research to minimize any potential dissemination of the instilled 
virus. 
6. No organ system disease (cardiac, hepatic, renal, endocrine) of a severity 
expected to limit an adequate systemic response to stress associated with 
experimental procedures. In general, this means normal organ function, except for 
biochemical abnormalities commonly seen with CF hepatic disease or glucose 
intolerance. Patients with CF-type insulin-requiring diabetes (not juvenile, ketotic- 
type diabetes) may be included if their insulin requirement is relatively low (<20 U 
NPH/day) and their diabetes is stable. 
Recombinant DNA Research, Volume 17 
[4891 
