Human Protocol (cont.) 
5. 
10. References 5-21 
1 . Background 
Cystic fibrosis is a recessive hereditary disorder caused by mutations of the 
cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is the 
most common lethal hereditary disorder in the USA (1) . The disease is confined 
mostly to the Caucasian and Hispanic population, although Blacks and Asians 
can be affected (1,2). Parents of affected individuals have no clinical mani- 
festations of CF. Males and females are equally at risk. In Caucasians, 1 in 
20 are heterozygotic carriers and the incidence is 1 in every 3000 live 
births. In Hispanics, the incidence is 1 in 7000 births. Each year, 1,300 
people are born in the U.S.A. with CF. There are an estimated 25,000 indivi- 
duals in the USA with CF, and approximately 50,000 worldwide (Cystic Fibrosis 
Foundation, Bethesda, Md. , personal communication). 
The clinical manifestations of CF are primarily in the lung, intestinal tract, 
pancreas and liver (1,3). The respiratory manifestations dominate, with thick 
mucus , chronic airway infections and inflammation beginning in early childhood 
and leading to progressive loss of lung function. Intestinal problems are most 
common in infants and include meconium ileus and intussusception. The exocrine 
glands of the pancreas are destroyed causing pancreatic enzyme deficiency and 
malnutrition. Diabetes can occur, as can liver failure. There is no cure for 
CF. The median survival in the USA is 29 years. Current treatments only ame- 
liorate symptoms. Therapies involve administration of antibiotics, physical 
chest manipulations for bronchial drainage, aerosolized DNase, physical ex- 
ercise, oral pancreatic enzymes, vitamins and dietary management. Lung trans- 
plantation has been carried out in CF individuals, but the efficacy of this 
procedure is not proven, and obtaining suitable donor organs is a major prob- 
lem (4). The cost of this disease is significant. Beyond the personal trage- 
dies for the affected individuals and their families, there are the associated 
costs of medical care. The average cost of drugs, diet supplements and medical 
equipment is $27,500 annually per patient. One to two hospital admissions per 
year are necessary for 38% of CF individuals. 
1.1 Respiratory Manifestations. Inherent in the concept that the morbidity and 
mortality associated with CF might be reversed by in vivo transfer of the 
normal CFTR gene to epithelial cells of the lung is the knowledge that the 
clinical manifestations of CF are dominated by abnormalities manifest on the 
epithelial surface of the airways (5). While CF is also characterized by ex- 
ocrine pancreatic insufficiency and high concentrations of sodium chloride in 
sweat, the pulmonary manifestations are, by far, the most common life threat- 
ening aspects of the disease. The earliest observed morphologic lesions are 
mucous obstruction of small airways and inflammation of the bronchiolar walls 
(6) . Bronchoalveolar lavage studies demonstrate neutrophil-dominated inflamma- 
tion in airway epithelial lining fluid of infants with CF as early as age 1 
(7) . As the disease progresses, there is inflammation of large and small air- 
ways, hypertrophy of submucosal glands, and a general increase in the numbers 
of secretory cells. There is obstruction of airways with mucous. Chronic in- 
fection of the airways develops, with accompanying acute and chronic inflamma- 
tion. With increasing cycles of mucus obstruction, infection and inflammation, 
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