Gene Therapy for CF using Cationic Liposome Mediated Gene Transfer: Phase I Trial 
hydration of exocrine pancreatic secretions, leading to pancreatic failure and inadequate levels 
of the pancreatic digestive enzymes crucial for absorption of a normal diet. Clinically, CF 
pancreatic insufficiency can be managed by administration of exogenous pancreatic dietary 
enzymes (for example, enzymes derived from porcine [Ultrase or Pancrease] sources) which are 
taken with meals. Prior to the development of exogenous pancreatic enzyme supplementation and 
other nutritional interventions, most CF patients died in infancy or early childhood of 
malnutrition. 
The ability to treat the nutritional aspects of CF led to an improved life expectancy of 
CF patients, and also to the need for improved therapies for the pulmonary sequelae of the 
disease. The lungs of CF patients undergo progressive fibrosis and scarring which may begin 
very early in life. Respiratory mucous in CF is thick, viscous and very difficult for patients to 
expectorate. Difficulty in clearing the respiratory mucous is associated with chronic pneumonia, 
including some forms of pneumonia caused by antibiotic-resistant organisms which are nearly 
pathognomonic for individuals with CF lung disease (e.g., respiratory colonization and 
pneumonia due to mucoid strains of multiply-resistant Pseudomonas aeruginosa l. Tenacious 
secretions and chronic respiratory infection lead to diminished pulmonary function (e.g., 
decreased FVC, decreased FEy^, loss of lung volume, and progressive mixed obstructive and 
restrictive lung disease. Most patients suffer from chronic progressive hypoxemia and air- 
hunger, and ultimately require repeated hospitalizations for intravenous broad-spectrum 
antibiotics to treat chronic pneumonia, as well as bronchodilators, oxygen supplementation, and 
chest physical therapy designed to mobilize inspissated pulmonary mucous and to improve 
aeration. Despite these standard measures of care, most CF patients die in young adulthood of 
respiratory failure. The current average life expectancy for a CF patient is 29 years (male) or 
28 years (female). Other organ systems are commonly effected by cystic fibrosis. For example, 
newborns with CF may develop meconium ileus, an obstruction of the bowel due to thick and 
inspissated neonatal stool. Abnormalities in secretions within exocrine glands of the female and 
male reproductive tract have been implicated as contributing to the high incidence of infertility 
among CF patients of reproductive age (greater than 95% of adult CF males are infertile and 
have significant azoospermia; a large number of adult CF females are also infertile). Exocrine 
pancreatic structural damage may result in loss of endocrine pancreatic islets and clinical 
diabetes, with the requirement for insulin administration. Chronic lung disease may secondarily 
lead to life-threatening hemoptysis requiring surgical intervention, or to right heart failure, which 
may be managed by appropriate diuretic or vasodilator therapy. 
I.B.2 Bioelectric abnormalities and relationship to CFl'K. 
Prior to identification of the CF gene, the finding that sweat levels of sodium and 
chloride were elevated in CF led to the suggestion that the disease was caused by a primary 
defect in ion transport (5,19). Studies of isolated, perfused human sweat ducts demonstrated 
defects in chloride transport in CF. Similarly, respiratory epithelial cells taken from CF patients 
lacked a cyclic AMP (cAMP) stimulated component of chloride transport. Since the discovery 
of the CFTR in 1989 (2-4), compelling evidence has accumulated that the CFTR functions, at 
least in part, as an apical membrane, cAMP stimuable chloride channel. Expression of CFTR 
in cells taken from CF patients, as well as in numerous heterogenous cell types, leads to the 
appearance of a cAMP dependent chloride channel (9, 10,20-22). Antisense experiments designed 
to eliminate CFTR lead to diminished Cl' transport in sweat duct cells, and point mutations or 
Recombinant DNA Research, Volume 18 
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