1992) and aerosolized alpha- 1 -antitrypsin as another approach to inhibit elastase (McElvaney 
et.al., 1991). In addition to defective chloride secretion, cystic fibrosis patients also have 
excessive sodium reabsorption by airway cells leading to excessive absorption of water. This 
has been treated with aerosolized amiloride to block the sodium channel (Knowles et.al., 1990). 
The effect of aerosolized amiloride seems to be relatively small and, therefore, administration 
of tricyclic nucleotides to stimulate chloride secretion has been developed as an adjunctive 
therapy (Boucher, 1992). At present, these approaches are experimental or in phase I trials. 
Much of the viscosity of CF sputum is due to the presence of DNA derived from decaying 
host neutrophils. It was reasoned that a reduction in viscosity by hydrolysis of such DNA might 
lead to improved clearance of secretions and improved pulmonary function in cystic fibrosis. 
Human pancreatic DNase (DNase I) was cloned and produced by recombinant techniques. 
Children’s Hospital, Cincinnati has been involved with Phase II and Phase III studies of the 
efficacy of this agent with regard to pulmonary function, quality of life, and dyspnea in cystic 
fibrosis (Fuchs et.al., 1992). Early results with DNAse therapy appear promising. Other new 
approaches to cystic fibrosis are under study and these include other protease inhibitors, anti- 
inflammatory agents such as alternate-day prednisone and daily administration of anti- 
staphvlococcal antibiotics (Keflex) starting at the time of diagnosis. Although these approaches 
may lead to amelioration of the progressive lung disease of cystic fibrosis, none of them is likely 
to result in a complete correction of the pathophysiological process that eventually results in 
respiratory failure and death. 
With the cloning and sequencing of the CFTR gene in 1989 came the possibility of correcting 
the basic defect in airway cells by somatic cell gene therapy. The respiratory epithelium has a 
large surface area and can be reached via the airway so it is amenable to gene therapy. The 
intent of this study is to utilize a replication deficient recombinant adenovirus as a viral vector 
to deliver the normal CFTR cDNA to airway epithelial cells with the goal of expressing this 
gene and correcting the chloride channel defect. This should lead to normal hydration of 
respiratory secretions and normalization of airway function. The technique will be evaluated 
initially in adults with CF who have mild to moderate lung disease (Crystal et.al., RAC 
proposal, 1992; Wilson et.al., RAC proposal, 1992; Welsh et.al., RAC proposal, 1992; and the 
current proposal). However, it is our belief that once the safety of this technique is established, 
the technique has more promise if used early in life, in the pediatric age group, prior to the 
development of airway fibrosis, micro-abscesses, and bronchiectasis. Thus, we feel that the 
development of a pediatric center for gene therapy of cystic fibrosis is an important priority. 
1.5 Measurements of Efficacy of Therapy for CF: When designing this protocol, we 
considered the measures of efficacy that can be used in cystic fibrosis. These include pulmonary 
function testing, imaging of the chest, growth and development, mucociliary clearance, 
inflammatory markers, potential difference measurement, in vitro studies of epithelial cell 
function, rates of hospitalization, and quality of life assessments. Nasal and tracheal potential 
difference measurements and laboratory studies of cells from the treated nostril and the treated 
lower airways will be used to establish correction of the chloride defect at the level of the 
membrane and individual cells. It is not anticipated that there will be a significant improvement 
in oxygen saturation or pulmonary function tests in response to treating one lobe and the trachea. 
However, it is anticipated that there will be improvement in mucociliary clearance from the 
treated lobe, and this might lead to correction of ventilation/perfusion abnormalities and, 
possibly, mucous plugging of small airways. Therefore, we propose to use perfusion scans 
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Recombinant DNA Research, Volume 17 
