Clinical Pearls & Morning Reports
Published November 1, 2023
Only half a century ago, most persons with a diagnosis of cystic fibrosis did not reach adulthood, but the median age of survival now is above 50 years in Canada, Australia, New Zealand, European countries, and the United States. Read the NEJM Review Article here.
Q: Describe the cellular functions that are affected by cystic fibrosis-causing variants.
A: Cystic fibrosis is an autosomal recessive disease caused by variants in the CFTR gene. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is involved in the regulation of transepithelial ion transport and water–electrolyte homeostasis in many organ systems. Cystic fibrosis–causing variants can result in premature termination codons with reduced or absent CFTR formation; premature degradation due to protein misfolding; abnormalities of channel gating, conductance, or both; reduced transcript, promotor, or splicing abnormalities; or accelerated turnover from the cell surface. The introduction of small-molecule drugs that address the underlying molecular defects, CFTR modulators, has resulted in unprecedented improvements in the health of many persons with cystic fibrosis.
Q: What is the most common cystic fibrosis–causing variant?
A: The number of CFTR variants that have been described as of this writing has increased to more than 2000; an ongoing effort supported by the Cystic Fibrosis Foundation has led to the annotation of more than 700 disease-causing variants. Deletion of three base pairs in CFTR leading to the loss of the amino acid phenylalanine at position 508 (F508del) of the protein is the most common cystic fibrosis–causing variant. Approximately 85% of all cystic fibrosis–related alleles in the United States are F508del.
A: The potentiator ivacaftor is effective in persons with cystic fibrosis carrying variants with residual CFTR expression in which channel conductance is reduced, such as the G551D variant. Although the exact mechanisms of action are unknown for the CFTR modulators, ivacaftor binds to CFTR and is thought to thereby increase the probability of opening the ion channel. In patients with F508del, combination therapy with corrector drugs that ameliorate the protein-folding defect and allow for transport of the channel to the cell surface and ivacaftor to improve channel gating are warranted to achieve clinical benefit. The first-generation corrector drugs lumacaftor and tezacaftor had modest benefits when combined with ivacaftor, and these benefits were observed only in persons with cystic fibrosis homozygous for F508del. In contrast, the triple-combination therapy elexacaftor–tezacaftor–ivacaftor benefits persons with cystic fibrosis who have either one or two F508del alleles and results in improvements in lung function exceeding those previously observed with ivacaftor in gating variants.
A: Given the impressive responses observed with ivacaftor and elexacaftor–tezacaftor–ivacaftor, these are now commonly referred to as highly effective modulator therapy, but CFTR chloride conduction, while improving, does not always normalize with these drugs and even more effective therapies could potentially become available in the future. Small molecule–based CFTR pharmacotherapy has been a huge success story, but there is an unmet need to develop therapies for persons with cystic fibrosis who are not eligible to receive these medications, who do not have a response to them, or who cannot receive them without adverse effects. For example, there is currently no CFTR-targeting therapy for cystic fibrosis caused by stop codon variants. Major efforts are under way to develop therapies such as nucleic acid–based therapies and alternative ion channel modulators that could potentially benefit all persons with cystic fibrosis, regardless of CFTR defect.