M.J. Welsh and A.E. Smith, RAC Application 
Ad2-ORF6/PGK-CFTR 
Item 5 - Clinical Protocol 
mortality rate for those patients is 50% (13). In contrast, those patients with mild lung disease (FEV1 > 
61%) have mortality rates of less than 5% in two years. Thus, assessment of mortality is impractical, as 
an endpoint in evaluation of therapy. 
Pulmonary function tests are frequently helpful as an endpoint but they are not without problems. They 
are subject to fluctuations by factors other than those being investigated. Perhaps evaluation by high- 
resolution chest CT, assessment of mucociliary clearance, and cardiopulmonary exercise testing may be 
more sensitive and specific. 
Use of Maxillary Sinus Epithelium to Assess Clinical Efficacy. 
An alternative to evaluate clinical efficacy is to use the maxillary sinuses. The upper airways of the nose 
and sinuses are almost universally involved by CF. In fact some have suggested that the absence of 
pansinusitis rules out a diagnosis of CF. Because we propose below to use the upper airways and 
sinuses in our evaluation of gene transfer for patients with CF and because knowledge of the upper 
airways in CF may be less widespread than knowledge of the intrapulmonary airways, we briefly review 
this subject with particular emphasis on the sinuses. Wine et al. (14) were the first to suggest use of the 
sinuses to evaluate therapeutic interventions in CF. 
Anatomy . The paranasal sinuses include the maxillary, frontal, ethmoid, and sphenoidal sinuses. All are 
involved by CF. The frontal sinuses rarely develop in CF patients, probably because of early onset of 
sinusitis which prevents pneumatization (15). In this proposal we focus on the maxillary sinuses which 
are uniformly involved in CF. The maxillary sinuses are connected to the nasal cavity through the 
maxillary sinus ostium. Nasal polyps have been reported in 10-32% of patients (16). 
Histology . The maxillary sinuses are lined by respiratory epithelium with ciliated cells, nonciliated cells, 
basal cells, and goblet cells (17). The epithelium in CF sinus disease is very similar to that observed in 
CF intrapulmonary disease. The histology of CF polyps are also similar to polyps associated with allergy 
in that there is mucus gland hyperplasia and mucus cysts. It has been suggested that CF polyps are 
distinct from allergic polyps because they have a relatively normal basement membrane and few 
eosinophils. However, such changes are also found in non-CF polyps and in blinded studies it is 
difficult to distinguish between polyps from the two diseases (18,19). 
Submucosal glands in upper airway epithelium . Careful quantitative evaluation of submucosal glands in 
upper and lower human airways indicates that glands in the sinus, nasal, tracheal and bronchial mucosa 
have similar histologic and morphology properties. The density of glands in the maxillary sinus of adult 
humans is 0.2 glands/mm^. For comparison, the density of glands in the adult trachea is 0.8- 1.0 
glands/mm^, but the density decreases as one moves distally from the trachea into the bronchi (20). 
Thus, the submucosal glands in the large and small airways are similar in morphology and number to 
those in the maxillary sinuses. 
Clinical presentation . Despite almost universal involvement of the sinuses in CF, the clinical presentation 
is often subtle. The majority of CF patients do not have symptoms as a result of sinus disease. When 
symptoms do occur, the most common are headache, nasal obstruction, purulent rhinorrhea, mouth 
breathing, snoring, postnasal drainage with cough, and constant throat clearing (16,21-23). Occasionally 
acute sinusitis may develop. 
Physiology . Most importantly for our studies, CF causes similar abnormalities of electrolyte transport in 
both upper and lower airway epithelia. Both manifest a lack of CFTR chloride channel function. In fact, 
the first evidence to suggest that CF airway epithelia had defective electrolyte transport was the study of 
upper airway epithelia (12). Chloride transport function can be assessed by measuring the voltage across 
the airway epithelium. This assay provides an easy and reliable measure of Cl' transport by the 
epithelium (12,24,25). The pathogenesis and pathophysiology of sinus disease and nasal polyposis in 
CF is thought to be identical to that of the pulmonary disease: altered respiratory tract fluid leading to 
impaired mucociliary clearance. 
Bacteriology . Studies in laboratory animals and a small number of humans have shown that the 
maxillary sinuses are normally sterile. But in CF, the maxillary sinuses are infected with the same 
organisms that cause lung disease: the most common is Pseudomonas aeruginosa (14,16,26). As_with 
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Recombinant DNA Research, Volume 18 
