Status of gene therapy for cystic fibrosis lung disease

Gene therapy for the treatment of cystic fibrosis should be a “natural”: Cystic fibrosis (CF) is a recessive disease associated with loss of function mutations in the CF transmembrane conductance regulator (CFTR) gene, which has a well-characterized gene product; heterozygotes, as predicted, appear to be phenotypically perfectly normal; the level of expression of CFTR in affected cells generally appears to be low; and the dysfunctional epithelial lining cells in the organ most affected by CF (the lung) are available for direct vector delivery via topical administration (1). However, despite an impressive amount of research in this area, there is little evidence to suggest that an effective gene-transfer approach for the treatment of CF lung disease is imminent. The inability to produce such a therapy reflects in part the learning curve with respect to vector technology and the failure to appreciate the capacity of the airway epithelial cells to defend themselves against the penetration by moieties, including gene-therapy vectors, from the outside world. This Perspective will focus on the issues that impact on moving this field forward. What is the target for CF gene therapy in the lung? Cystic fibrosis affects the conducting airways of the lung and not the alveolar surfaces. The airways in general consist of a “large” airway (bronchial) region that is lined by a pseudostratified columnar superficial epithelium and contains numerous submucosal glands, and a “small” airway (bronchiolar) region that is lined by a simple columnar epithelium and is devoid of glands. Central issues for CF gene therapy are which region (large vs. small) and which tissue (superficial epithelium vs. glands) should be targeted. Obviously, the answer to this question requires knowledge of the pathogenesis of CF lung disease. As reviewed earlier in this Perspective series (2, 3), this is a controversial issue. Although the so-called “isotonic” and “hypotonic” airway surface liquid theories have different predictions on the pathogenesis of CF airways infection, both agree that defects in the superficial epithelium may initiate CF lung disease. However, studies from other model cell culture systems, like Calu-3 cells and cultured gland acini (4), predict that there may be abnormalities in gland volume/compositional (HCO3 ‐ ) regulation in CF that may be more important in the pathogenesis of CF airways infection. This debate can also be viewed in the context of the individual cell types in the airways. Advocates of the importance of the superficial epithelium in CF pathogenesis likely would