Cystic fibrosis

Abstract

Cystic fibrosis is an autosomal recessive, monogenetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene defect was first described 25 years ago and much progress has been made since then in our understanding of how CFTR mutations cause disease and how this can be addressed therapeutically. CFTR is a transmembrane protein that transports ions across the surface of epithelial cells. CFTR dysfunction affects many organs; however, lung disease is responsible for the vast majority of morbidity and mortality in patients with cystic fibrosis. Prenatal diagnostics, newborn screening and new treatment algorithms are changing the incidence and the prevalence of the disease. Until recently, the standard of care in cystic fibrosis treatment focused on preventing and treating complications of the disease; now, novel treatment strategies directly targeting the ion channel abnormality are becoming available and it will be important to evaluate how these treatments affect disease progression and the quality of life of patients. In this Primer, we summarize the current knowledge, and provide an outlook on how cystic fibrosis clinical care and research will be affected by new knowledge and therapeutic options in the near future. For an illustrated summary of this Primer, visit: http://go.nature.com/4VrefN.

Figure 1.

Cystic fibrosis in the United States. a | The number of patients reported in the annual reports of the CF Foundation in 5 year intervals from 1998 to 2013. The figure notes a fairly substantial increase in the number of people living with cystic fibrosis in the US CFF Patient Registry, which is likely attributable to improved survival of patients during this 15 year period and not merely newly diagnosed patients. b | The numbers of newly diagnosed patients in each of the given years over time.

Figure 2.

Structure of CFTR. a | Linear structure of the protein. b | The cystic fibrosis transmembrane conductance regulator (CFTR) protein is comprised of two, six span membrane-bound regions each connected to a nuclear binding domain (NBD1 and NBD2), which bind ATP, as well as a regulatory (R) domain that is comprised of many charged amino acids. The channel opens when its R-domain is phosphorylated by protein kinase A and ATP is bound at the NBDs.

Figure 3.. The mucociliary transport defect in cystic fibrosis.

a | In the healthy state, adequate airway surface homeostasis enables effective transport of mucus extruding from the airway surface goblet cells and submucosal glands. Appropriate bicarbonate and pH regulation enable normal mucus to form, which facilitates the formation of a two-layer gel that optimizes mucociliary clearance and airway defence. b | Depletion of the airway surface liquid occurs through the absence of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion accompanied by tonic fluid absorption via the epithelial sodium channel (ENaC; inset). CFTR-dependent liquid desiccation decreases airway surface liquid (ASL) depth including the periciliary layer (PCL), ultimately contributing to mucus stasis. Decreased bicarbonate transport contributes to an acidic pH. Abnormally adherent mucus also emerges from the glands in cystic fibrosis, and can become fixed to the gland orifice or the originating goblet cells. These events contribute to a proinflammatory airway environment that further accelerates pathogenesis.

Figure 4.. Diagnosing cystic fibrosis: nasal potential difference measurement.

Representative nasal potential difference tracings from a healthy control (blue) and a patient with cystic fibrosis (red). The nasal mucosa is sequentially perfused with Ringer’s solution (an isotonic solution relative to the bodily fluids), Ringer’s solution with amiloride to block the epithelial sodium channel (ENaC), chloride-free solution with amiloride, chloride-free solution with amiloride and isoproterenol to activate the cystic fibrosis transmembrane conductance regulator (CFTR), and finally the addition of ATP to activate non-CFTR-dependent anion transport. The change in potential difference upon addition of amiloride is used to estimate sodium transport, which is elevated in cystic fibrosis. The change in potential difference with chloride-free isoproterenol is used to measure CFTR-dependent anion transport, which is reduced in cystic fibrosis. Patients with mild phenotypes of cystic fibrosis generally exhibit intermediate results.

Figure 5.. Currently available therapies to treat patients with cystic fibrosis.

Although the therapies are based on the cellular mechanism, the details on how these compounds exert their effects at the molecular level are not entirely clear for most drugs, a consequence of their identification from high-throughput screening programmes that focus on the functional readout rather than mechanism of action. Most compounds generally address a specific aspect of the molecular defect and do not, therefore, alleviate the effects of all classes of CFTR mutations. For example, the CFTR potentiator ivacaftor directly activates CFTR and is currently licensed in most countries (except New Zealand) for patients with class III (gating) mutations. Hypertonic saline increases airway surface liquid, which is reduced in patients with cystic fibrosis as a consequence of defective chloride and increased sodium absorption. Dornase alfa cleaves extracellular DNA, thereby reducing the viscosity of airway secretions. Inhaled tobramycin and aztreonam are used as chronic maintenance therapy in patients with chronic Pseudomonas aeruginosa infection. Azithromycin has multiple potential modes of action, but mainly ameliorates airway inflammation — as is the case for high dose ibuprofen, which reduces neutrophil influx into the airways.

Figure 6.. Emerging approaches to address the ion channel abnormalities in cystic fibrosis.

The main target for therapeutics is cystic fibrosis transmembrane conductance regulator (CFTR), which can be replaced through gene therapy, or increased in concentration on the cell surface. Increased CFTR concentration could be achieved through translational readthrough therapy (class I mutations), correction of intracellular trafficking (class II mutations) or potentiation of its function (class III mutations, potentially class IV and class V). Alternatively, a calcium-activated chloride channel could be a therapeutic target; this channel is activated through the P2Y2 receptor (the natural ligand being ATP). Finally, as sodium absorption is upregulated in the airways of patients with cystic fibrosis, blocking the epithelial sodium channel (ENaC) could be of benefit to increase airway surface liquid.