use is increasing to help keep the airways clear. Bronchodilator therapy may 
give symptomatic relief but the response is not universal . The value of other 
therapeutic strategies such as mucolytics , expectorants, chronic corticoster- 
oids or other anti-inflammatory agents remains unproven. Early vaccination for 
measles and pertussis are recommended as is yearly influenza vaccination. In- 
patient therapy is necessary when there are exacerbations of pulmonary infec- 
tions or complications of CF lung disease such as hemoptysis, pneumothorax, 
respiratory failure, pulmonary hypertension, and cor pulmonale. For acute 
infections requiring hospitalization, empiric antibiotic therapy is necessary 
at first but is then based on culture and sensitivity results from respiratory 
secretions . Patients with acute infections are also given increased postural 
drainage and chest percussion, bronchodilator therapy, and occasionally corti- 
costeroids. The treatment of the lung complications of cystic fibrosis does 
not differ from the treatment of other chronic lung disease states. 
1.3 Rationale for Gene Therapy. The identification of the CFTR gene in 1989 
(16-18) opened the door to strategizing therapies for CF in which the normal 
gene would be transferred to somatic cells of individuals with CF, thus re- 
versing the biologic abnormalities consequent to mutations of the two parental 
CFTR genes. Because the respiratory manifestations of CF dominate the clinical 
picture, it is the most rational target for gene therapy for this disorder. 
The concept that the respiratory manifestations of CF are a good candidate for 
gene therapy is based on several facts. First, the respiratory disease is con- 
fined to the epithelium of the airways. In vitro studies have demonstrated 
that the CFTR protein is a Cl' channel that modulates the secretion of Cl* in 
response to elevations of intracellular cAMP (19-23) . Mutations of the CFTR 
gene render epithelial cells unable to modulate Cl' permeability through the 
cAMP pathway (24-27). It is this biologic abnormality that is believed to 
cause the respiratory manifestations of the disease (3,28,29). Second, in 
vitro studies have shown that transfer of the normal CFTR cDNA to epithelial 
cell lines derived from individuals with CF can override this abnormality and 
permit the cells to secrete Cl* in response to increased intracellular cAMP 
(22,23). Finally, the lethal consequences of mutations of the gene occur al- 
most exclusively in the lung (3). Together, these concepts suggest the feasi- 
bility of somatic gene therapy for CF, i.e., it should be possible to correct 
the pulmonary manifestations caused by mutations of the CFTR gene by directly 
transferring the normal human CFTR cDNA to airway epithelial cells. 
The architecture of the airways demands that if gene therapy for the respira- 
tory manifestations of CF is to be successful, the transfer of the normal CFTR 
cDNA to the airway epithelium will have to be carried out in vivo via the air 
side of the epithelium. On clinical and technical grounds it is not possible 
to use ex vivo strategies to remove the epithelium, insert the normal cDNA and 
replace the existing epithelium. The adult human airways have a surface area 
of 1-2 m 2 . There are at least 6 major epithelial cell types, with the majority 
of the cells terminally differentiated. Human airway epithelial cells can be 
cultured, but the methods are primitive, the differentiated state of the cells 
is not necessarily the same as that in vivo . the growth factors are not known, 
and neither the normal cell ontogeny, nor the airway epithelial stem cell popu- 
lation is clearly defined (30). Most importantly, the dichotomous branching 
nature of the airways precludes any strategies to remove the epithelium and/or 
introduce corrected autologous airway epithelial cells. Together, these facts 
argue strongly for an in vivo approach to gene therapy. The anatomy dictates 
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