Cystic Fibrosis · CF

Description

Cystic fibrosis (CF) is an inherited disorder of epithelial chloride and bicarbonate transport caused by pathogenic variants in CFTR, the gene encoding the cystic fibrosis transmembrane conductance regulator. Two damaging copies of CFTR produce a chloride channel that is missing, misfolded, or dysfunctional at the apical membrane of secretory epithelia. Airway surface liquid becomes dehydrated and viscous, mucociliary clearance fails, and chronic infection with Pseudomonas aeruginosa, Staphylococcus aureus, and other organisms drives progressive bronchiectasis. The same channel defect produces pancreatic ductal obstruction, leading to exocrine pancreatic insufficiency in roughly 85 percent of people with CF, along with CF-related diabetes, intestinal complications including meconium ileus and distal intestinal obstruction syndrome, congenital bilateral absence of the vas deferens in men, and progressive lung disease. Inheritance is autosomal recessive. The most common pathogenic variant in populations of European ancestry is F508del.

Reported live-birth incidence in non-Hispanic white populations is approximately 1 in 3,500, with substantially lower rates in populations of African, Hispanic, and Asian ancestry. The CFTR gene was cloned by Lap-Chee Tsui, Francis Collins, and John Riordan in 1989. Detection in the United States is by newborn screening on the dried blood spot, using immunoreactive trypsinogen as a first-tier marker followed by CFTR DNA analysis. Sweat chloride measurement remains the diagnostic gold standard, with values at or above 60 mmol/L confirming the diagnosis. CF has been on the Recommended Uniform Screening Panel since its initial 2006 formulation, and all US states had adopted CF newborn screening by 2010.

Treatments to date

Standard supportive care includes airway clearance, inhaled hypertonic saline, dornase alfa (Pulmozyme, FDA approved 1993), inhaled tobramycin for chronic Pseudomonas infection, pancreatic enzyme replacement with a fat-soluble vitamin regimen, nutritional support, and aggressive treatment of pulmonary exacerbations. The CF Foundation accelerated drug development through its therapeutics development model from the late 1990s onward, partnering with Vertex Pharmaceuticals on small-molecule discovery for CFTR.

CFTR modulator therapies have changed the trajectory of CF for the substantial majority of people with the disease. Ivacaftor (Kalydeco) was FDA approved in January 2012 for people with the G551D gating variant, and indications were later expanded to additional gating and residual-function variants. Lumacaftor/ivacaftor (Orkambi) was FDA approved in July 2015 for people homozygous for F508del. Tezacaftor/ivacaftor (Symdeko) was FDA approved in February 2018. Elexacaftor/tezacaftor/ivacaftor (Trikafta, marketed as Kaftrio in the European Union) was FDA approved in October 2019 for people 12 and older with at least one F508del allele, and the indication was expanded to ages 6 and older in 2021 and to ages 2 and older in April 2023. Trikafta is now eligible for an estimated 90 percent of the CF population in the United States. Real-world data show large reductions in pulmonary exacerbations and sustained improvement in lung function relative to pre-modulator baselines (Middleton et al., New England Journal of Medicine, 2019).

Lung transplantation remains an option for people with end-stage lung disease that does not respond to or cannot be treated with modulators. Several gene therapy and genetic therapy programs targeting the underlying CFTR defect, including mRNA delivery and gene editing, are in early-phase trials, and an estimated 10 percent of the CF population without modulator-responsive variants remains the principal target population for these efforts.