CFTR is also a regulator of many ion transport pathways (including non-CFTR chloride channels, sodium, bicarbonate, ATP, glutathione, and, potentially, other small molecules), and this protein helps to establish the content of the airway surface liquid (ASL) and of submucosal glandular secretions.^1–7 Loss of CFTR activity in the airways initiates a chain of events including reduction in the ASL volume, dehydration and thickening of glandular mucus secretions, airway obstruction, chronic bacterial infection, and relentless inflammation, which together contribute to the development of bronchiectasis and eventual respiratory failure. Advances in supportive care have led to a steady increase in the average life expectancy of people with CF, with recent statistics demonstrating a median survival of over 37 years (CFF registry statistics, 2005). CF remains a devastating illness for many patients, with substantial numbers succumbing to the disease in childhood and early adulthood.

Pulmonary therapies are aimed at treating disease symptoms, including:

• regular chest clearance (through daily chest percussion—predominately by hand or vest);
• mucolytics (e.g. nebulized recombinant human deoxyribonuclease (rhDNase);
• antibiotics (including cycled use of tobramycin for nebulization (TOBI^®) in patients with respiratory tract cultures positive for Pseudomonas aeruginosa, extending to oral and/or intravenous antibiotics for acute pulmonary exacerbations); and
• macrolide therapy, bronchodialators, and anti-inflammatories (oral and inhaled).^8–14

Cumulatively, these therapies have led to a dramatic increase in the survival of CF patients. They also can create substantial and often confusing treatment regimens for patients who require regular daily attention for clear clinical benefits. Compliance can be extremely challenging across all age groups of CF patients and their families for a variety of reasons, and the limited number of comparative trials (that might simplify treatment) leaves CF care-givers with little evidence to guide choices between therapies. The result is often an escalating care plan as new therapies arise or symptoms increase, with the potential to further complicate daily care. Accumulating evidence from patient outcomes in several European CF care centers, and more recently from studies performed in the US, are leading to a more preventive, pre-symptomatic approach to CF care.^15–22 This shift in care philosophy is well timed with the adoption of CF newborn screening in the US and abroad, and will be of significant benefit to CF patients and their families.^23,24 It also raises many questions regarding how to adapt therapies to the infant and toddler CF population, and how to demonstrate efficacy in these difficult to study patients.

Understanding of Cystic Fibrosis Airway Biology—Application to New Pulmonary Strategies
The CFTR gene was identified in 1989, and since that historic achievement an immense amount of work has been performed to understand how this single genetic defect results in the complex clinical picture that characterizes CF.^1–3 While there are many questions that remain to be answered regarding the steps between genetic defect and airway disease, the breadth of knowledge gained regarding CF pathogenesis has helped researchers to identify numerous strategies directed toward central causes of CF. These approaches include: normalization of sodium, chloride, and/or mucociliary transport in the airways; direct gene transfer to the airway epithelia; and restoration of mutant CFTR function through genotype-specific, small-molecule therapies. Each of these therapeutic strategies has advanced to clinical trials in CF patients, and positive results have the potential to extend CF therapy from ‘symptom-based’ to treatment of the underlying causes of CF lung disease.

Normalization of Sodium, Chloride, and/or Mucociliary Transport
Normally, the composition and volume of the ASL layer that bathes and maximizes ciliary function is delicately balanced between sodium absorption, which is believed to drive chloride and water transport from the luminal to the blood compartment, and chloride secretion, which helps to hydrate the lumenal compartment.^25–33 Evidence also suggests that the source of this fluid is in large part in the submucosal glands, where CFTR expression is significantly higher than in surface epithelial cells.^34–37 In the CF airway, loss of CFTR function leads to loss of cyclic adenosine monophosphate (cAMP)-stimulated chloride conductance via CFTR and the outwardly rectified chloride channel (ORCC), which is positively linked to CFTR,38 alteration of submucosal gland secretions, and enhanced sodium absorption from the epithelial surface. The increase in sodium transport is believed to drive dehydration of the ASL compartment, which perturbs normal mucociliary clearance and sets the stage for the development of mucus plaques that adhere to the underlying epithelium.^32,39 This mucus stasis has been postulated to make the CF airway susceptible to bacterial infection, and potentially begin the cascade of CF lung disease. This system is not without potential back-up ion transport pathways that are protective. Work by Boucher and colleagues supports a model in which ATP released from the airway epithelium in response to shear stress (such as the breathing cycle or coughing) can bind to P2Y2 receptors that are normally found on the apical surface of airway epithelial cells.^32,40–44 Stimulation of these G-proteincoupled receptors raises cell calcium, which in turn activates calciumactivated chloride channels (CaCCs) and can partially restore mucociliary clearance. However, over time this system is believed to fail (possibly due to accumulated damage and/or negative effects of recurrent viral infections), leading to the typical sequelae of CF lung disease.^32,45