State-of-the-art techniques are yielding information concerning normal and abnormal CFTR structure, potentially providing targets for drug therapy (3
). CFTR function continues to be an important focus of investigation that includes interactions among CFTR domains as well as with associated proteins and signaling pathways (6
). New technologies, including small interfering RNAs and high-throughput screening, have been used to understand CFTR pathophysiology and to develop small molecules that improve CFTR function (8
). In addition, studies of the use of stem cells to repopulate the airway offer promise of cell-based therapy in CF (11
Clinical outcome in CF is variable, even after controlling for CFTR mutation. This has led to the search for modifier genes. In a landmark study, Drumm and coworkers carefully examined putative modifier genes in large populations of patients with very good pulmonary outcome as well as in those with poor outcome (13
). They found that of 10 previously reported modifier gene candidates, only mutations in the gene encoding transforming growth factor β1 (TGF-β1) could be conclusively demonstrated to influence outcome. Increased expression or activity of TGF-β1 was associated with poorer outcome, providing more evidence for a role for the host response to infection in CF. Although this report examined previously identified modifier genes, new candidate genes have also appeared. A particularly intriguing candidate is a key antiinflammatory mediator, macrophage inhibitory factor (MIF), as reported by Plant and coworkers (14
). In a study of several hundred patients with CF, a novel polymorphism conferring less promoter activity in MIF was associated with decreased Pseudomonas
infection and less pancreatic insufficiency, further confirming an important role for inflammation in CF outcome.