heterozygotes (carriers) are normal with regard to lung function, is that the 
introduction of the complementary DNA (cDNA) coding for the normal CFTR 
protein will convert CF cells to the heterozygous forms that function normally. 
Unlike the therapeutic approaches envisioned for the treatment of bone marrow 
disorders, it appears to be improbable that cells can be harvested from the cystic 
fibrosis lung, genetically corrected, and returned to the host. The complex 
branching pattern of the lung would appear to preclude this approach. However, it 
is possible that DNA vectors can be delivered for correction directly to the lung by 
aerosol or direct instillation. 
II.B.2. Target for CF lung gene therapy 
Design of rational approaches of gene therapy for CF lung disease requires 
an understanding of the distribution of CFTR expression in the non-CF lung. 
Extensive experience with the clinical and pathological manifestations of CF suggest 
that the primary abnormalities in the lung relate to the defects in mucociliary 
clearance (see section II. A). The prediction, therefore, is that the CF gene is 
normally expressed in the conducting airway rather than the airspace. 
The human airway is a network of branching structures that conduct air from 
the alveolar sacs where gas exchange occurs to the external environment (29). The 
general structure of the airway varies as it branches from the most proximal site 
below the larynx (i.e., the trachea) to the most distal terminal bronchioles. Proximal 
airways are lined with a surface epithelium that is pseudostratified, containing a 
layer of squamous cells resting on the basal lamina (called basal cells) with a variety 
of columnar cells including ciliated cells, goblet cells, undifferentiated cells and 
secretory cells with electron dense granules. Basal and goblet cells are believed to 
be progenitors that are capable of self-renewal and differentiation into ciliated cells. 
Areas of the proximal airway surrounded by cartilage also contain 
submucosal glands which consist of a network of secretory tubules and associated 
ducts (30). These glands deliver into the airway lumen a complex seromucous 
secretion essential for mucociliary clearance. The most distal component of the 
submucosal glands consists primarily of serous tubules and serous acini. The serous 
cell has exocytotic vesicles that contain a mixture of bactericidal proteins. The 
mucous tubules, which lie proximal to the serous cells, secrete highly viscous mucous 
glycoproteins. All serous secretions must pass through the mucous tubules on the 
way to the airway. Seromucous secretions move from the tubules into collecting 
ducts which are lined by simple columnar epithelial cells rich in mitochondria. The 
high mitochondrial content of these cells suggests they may play a metabolically 
active role in regulating water and ion concentrations in ducts. Seromucous 
secretions reach the respiratory surface by passing from collecting ducts which, as 
extensions of the surface mucosa, are lined by a pseudostratified, ciliated 
epithelium. 
The distal airway is normally void of submucosal glands and has a much 
simpler surface epithelium which is cuboidal in structure. There are essentially two 
types of cells in the distal airway: ciliated cells and Clara cells which contain 
electron dense secretory granules and are believed to be progenitors. 
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Recombinant DNA Research, Volume 17 
