M.J. Welsh and A.E. Smith, RAC Application 
Ad2-ORF6/PGK-CFTR 
Item 5 - Clinical Protocol 
CF lung disease, antipseudomonal antibiotics alone are not sufficient to eradicate sinus infection in 
patients with CF. 
Radiology . Coronal sinus computed tomography (CT scans) are the most sensitive way to diagnose and 
evaluate sinus disease. In the vast majority of cases maxillary sinuses are opacified as a result of mucosal 
thickening and thick tenacious secretions which occupy the lumen. The periosteum can also be involved 
(14,27). 
Treatment In most asymptomatic cases, treatment of sinus disease is not required. When treatment is 
required, antibiotics are usually administered. But in most patients antibiotic treatment alone is not 
successful, and surgical drainage is performed. While 50-70% of non CF patients with chronic sinusitis 
respond well to endoscopic sinus surgery, nearly all tend to relapse after initial success. For example, in 
a three year prospective study, seven CF patients underwent endoscopic polypectomy and enlargement of 
the maxillary antra (28). There was good relief initially, but a coronal CT scan performed three years 
after surgery revealed severe pansinusitis and opacification of maxillary sinuses. 
Relationship between sinus and lung disease . Chronic colonization of the paranasal sinuses with 
Pseudomonas and other organisms may contribute to CF lung disease. Drainage of organisms from the 
sinuses into the dependent lung is a source of colonization and inflammation. A similar situation occurs 
with sinus disease in non CF subjects who develop secondary cough, bronchial reactivity, and asthma 
(29). CF patients who have undergone heart-lung transplantation can develop recurrent Pseudomonas 
bronchitis in the transplanted lung. But treatment with maxillary sinus antrostomy and repeated sinus 
lavage with antibiotics produced significant improvement and prevented the lung disease (30). In 
addition, adult CF patients who underwent bilateral Caldwell-Luc procedures to remove the maxillary 
sinus mucosa showed significant improvement in both local and respiratory symptoms and had a 
decreased frequency of hospital admission for pulmonary exacerbations (31). These observations 
suggest that sinus disease may contribute to pulmonary exacerbation in patients with CF. 
Safety advantages of using upper airway epithelium . Use of the sinus epithelium will provide several 
safety advantages, a) It will allow us to use a relatively small total amount of virus because we can apply 
it to a limited area. As a result, we will be able to obtain a great deal of useful information, but at the 
same time, use of a small amount of virus will minimize the risk, b) Upper airways have the advantage 
that the epithelium is more readily accessible than that in the lower airway for the frequent studies required 
to test safety and efficacy. Because it is more accessible, there will be less patient discomfort and risk, c) 
If significant inflammation or cytotoxicity should develop as a result of administration of the recombinant 
virus, the consequences to the patient will be much less severe if they occur in the upper airways than if 
they occur more generally in the lung. 
Advantages for assessing efficacy . Use of the maxillary sinus epithelium provides several advantages for 
assessing the clinical efficacy of gene transfer. As we indicate above, because CF is a chronic disease, 
testing clinical efficacy of gene transfer by assessing lung disease may be difficult, yet knowledge that the 
clinical defect can be corrected is critical to future efforts at gene transfer for CF lung disease. Testing 
clinical efficacy in the maxillary sinuses has the advantage that the tests to assess function (sinus CT and 
cell counts and inflammatory mediators in sinus washes) may be more sensitive and yet less invasive than 
those required to test clinical efficacy in the lung. 
Resolution of chronic sinusitis . Resolution of chronic sinusitis involves not only the elimination of 
chronic bacterial growth but also the re-establishment of mucociliary transport and the resolution of 
edema. In non CF patients this usually takes 4-6 weeks. We are not certain how long it may take to 
observe improvement of CF sinus disease after transfer of CFTR cDNA, but we expect that if clearing is 
to occur, it may require from 6 weeks to 6 months. Because the sinuses are markedly abnormal by 
coronal CT scans, improvement over baseline may be obvious to independent radiologists. Quantitative 
cultures of sinus lavage for Pseudomonas aeruginosa and measurement of inflammatory mediators will 
also be valuable endpoints. 
Summary . In summary, we believe that a trial of clinical efficacy using the maxillary sinuses has 
significant advantages: a) The maxillary sinuses provides an excellent model of lower airway epithelium 
in CF. They have similar histology and submucosal glands, and the physiology and pathophysiology are 
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