Although CF affects several major organs, the associated lung disease is the major factor affecting morbidity (in the developed world) and is the target for gene therapy. A key question is to what extent do normal levels of CFTR expression need to be matched in order to have a therapeutic effect?
For example, heterozygote carriers of CF only express 50 % of the normal level of CFTR yet do not develop the pulmonary disease. Individuals with rare splice variant mutations express as little as 10 % normal CFTR but do not present with pulmonary disease (Chu et al. 1993). Importantly it has been established that there is a non-linear relationship between the expression of the gene and correction of the cAMP Cl- defect. It has been estimated that the epithelium of the conducting airways contains 1-2 copies of CFTR mRNA per cell (Chu et al. 1993), although substantial amounts of CFTR mRNA have been detected in the serous cells and ducts of the sub-mucosal glands in the conducting airways (Engelhardt et al. 1992).
In situ hydridisation studies have detected CFTR mRNA in approximately 5 % of cells in the bronchioles and alveolar regions (Engelhardt et al. 1994). The low level, but widespread pattern of CFTR gene expression in the airways would suggest that most cells require CFTR gene transfer to correct the physiological defect. However, the expression of CFTR in only 6-10 % of cells in a polarized CF epithelium was sufficient to correct the Cl- ion transport defect (Johnson et al. 1992), leading to a widely held belief that a modest 5 % correction of the total CFTR expression in the adult lung by gene therapy could be sufficient for the correction of the disease (Dorin et al. 1996).
However, this assumption is based on cell culture models, and transgenic mice that do not develop CF pulmonary disease. Furthermore, far higher levels of correction may be required to correct the Na+ absorption defect associated with ENaC (Johnson et al. 1995).
Fundamentally therefore, it remains unclear which cells in the lung need to express CFTR to prevent CF pulmonary disease. The assumption must be that wherever CFTR is expressed, it has a role in CF lung disease and is a potential target cell for CF gene therapy.