III.C. One-page abstracts (scientific and non-technical) 
Scientific 
Cystic fibrosis (CF) is an autosomal recessive disease that reflects mutations 
in the CFTR gene. Multiple mutations in this gene have been detected that lead to 
a protein (CFTR) that is abnormally metabolized, dysfunctional, or both. The full 
spectrum of the activities of the gene product have not been defined, but it is clear 
that CFTR can act as a cAMP-regulated Cl" channel. This type of defect is 
consistent with the physiologic characterization of CF epithelia, which has revealed 
abnormalities in salt and water transport. In the lung, abnormalities in epithelial 
salt and water metabolism lead to abnormal mucociliary clearance. This defect in 
clearance represents a major failure of lung defense and leads ultimately to 
infection of the lung with Staphylococcus aureus , Pseudomonas aeruginosa, and other 
bacterial organisms. The chronic inflammatory response to this persistent 
intraluminal bacterial infection leads to protease-induced destruction of airway 
walls and finally, lung failure. More than 95% of CF patients die of lung disease. 
The clinical therapy of CF lung disease is limited to agents designed to 
promote clearance of secretions from the lung and antibiotics to treat the chronic 
bacterial infection. Recent laboratory demonstrations that introduction of the 
normal CFTR cDNA into CF cells corrects the ion transport defects of these cells 
has led to the hypothesis that gene therapy in the lung can be an effective, novel 
mode of therapy for this lung disease. The classic gene transfer vectors, e.g., 
retroviruses, appear to be not well suited for therapy of lung disease because of the 
low proliferation rate of airway epithelia in vivo. Recently, adenoviruses, which 
have a natural tropism for airway epithelia, have been genetically modified (El- 
deleted) in an attempt to reduce potential toxicity of this virus and provide space for 
the CFTR cDNA. A series of in vitro studies have shown that this vector is highly 
efficient for transferring CFTR into airway epithelial cells in culture and correcting 
the CF defect. Further, studies in whole animals appear to indicate that this mode 
of gene transfer is associated with a low degree of toxicity. 
The present study is a dose-effect study designed to test for the safety and 
efficacy of El-deleted recombinant adenovirus containing the CFTR cDNA under a 
CMV-p actin promoter in CF nasal epithelia. The nasal epithelium was selected for 
study because it exhibits the epithelial defects characteristic of CF, allows the 
administration of a low volume of virus to an accessible area of the epithelium, and 
is highly suited for multiple studies designed to measure toxicity and efficacy. A 
single dose will be administered to the nasal turbinate region of CF patients, with 
doses ranging from 10° to 10 11 pfu/ml. Three patients will be selected for each 
dose (10 ,3 x 10 , 10 11 ). Beginning 24 hr after vector instillation, assessment of 
the effects of virus on safety will be sought utilizing nasal lavage for measurement of 
inflammatory cells, mediator release, and viral shedding, and intermittently by 
biopsies designed to evaluate nasal epithelial morphology and intracellular viral 
replication. Efficacy will be tested by restoration of electrolyte transport as 
measurement by the in vivo PD technique (a non-invasive measurement). These 
studies will be completed by immunocytochemical studies designed to test for 
expression of CFTR in nasal epithelial cells. The goal is to define the safety and 
efficacy of the various doses as a function of time, with the ultimate goal of using 
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Recombinant DNA Research, Volume 17 
