CF Therapy Kaftrio rescues chloride and bicarbonate deficits in gastrointestinal tissues
Kaftrio triple combination therapy restores the function of CFTR – the defective protein in cystic fibrosis (CF) – and the associated chloride and bicarbonate flux in the gastrointestinal “mini-organs” derived from a patient carrying the la mutation. most common cause of cystic fibrosis, study finds.
These findings highlight the benefits of Vertex Pharmaceuticals‘ Kaftrio, sold as Trikafta in the United States, beyond the most studied chloride flux. They suggest it may also help counteract the abnormally acidic environment resulting from CFTR-dependent loss of bicarbonate secretion that contributes to the obstruction and inflammation of thick mucus.
Cystic fibrosis is caused by defective CFTR, a channel protein that normally controls the flow of water and ions through cells, due to mutations in the CFTR uncomfortable. CFTR deficiency leads to the buildup of thick, sticky mucus that clogs the airways and digestive tract.
Although this is due to the deficient transport of two important ions, chloride and bicarbonate, most studies have focused on the restoration of chloride flux alone.
Notably, bicarbonate is needed to maintain proper pH, or acid-alkaline balance, on cell surfaces, and low levels have been shown to increase organ acidity (lower pH) and alter the properties of mucus. This promotes the production and blockage of thick mucus and increases susceptibility to bacterial infections.
Now, a team of researchers in the Netherlands has assessed whether the approved Kaftrio therapy for cystic fibrosis restored chloride and bicarbonate transport in gastrointestinal organoids derived from a cystic fibrosis patient carrying F508del, the mutation causing the most common cystic fibrosis.
Kaftrio combines three oral cystic fibrosis drugs: elexacaftor and tezacaftor – designed to help defective CFTR reach the cell membrane by correcting its structural deficit – and ivacaftor, a so-called CFTR potentiator that aims to open the channels blocked allowing the transport of water and ions.
In Europe it is approved for CF patients with at least one F508del mutation, also known as Phe508del, while in the United States its label has been extended to patients with other specific mutations.
Patient-derived organoids are 3D “mini-organs” that better mimic diseased tissue and are considered useful in predicting the clinical benefits of therapy. The researchers developed intestinal organoids and cholangiocytes, the cells that line the bile ducts – tube-like structures in the liver that carry bile to the small intestine to aid digestion.
Organoids from a healthy donor were also developed as controls.
Results showed that Kaftrio significantly increased CFTR-mediated chloride and bicarbonate transport in intestinal organoids derived from CF patients, reaching 50% of the response seen in control organoids.
The treatment also resulted in a chloride-to-bicarbonate transport ratio similar to that seen with healthy CFTR protein and comparable to that previously reported for laboratory-grown cystic fibrosis lung models.
These findings suggest that Kaftrio alters the conformation of the F508del-CFTR protein “so that its ion selectivity closely mimics that of the F508del-CFTR protein.” [healthy] channel,” the researchers wrote.
In CF biliary organoids, Kaftrio significantly increased CFTR-mediated chloride transport, but not bicarbonate.
Further analyzes showed that, unlike intestinal cells, cholangiocytes displayed CFTR-independent chloride and bicarbonate transport that was mediated by calcium-gated chloride channels.
It has been found that cholangiocytes secrete bicarbonate primarily through AE2, a chloride-bicarbonate exchange protein, which is mediated by CFTR-mediated chloride transport.
“This model implies that Phe508del-CFTR-mediated restoration of chloride secretion is sufficient to restore bile bicarbonate secretion,” the team wrote.
Notably, CFTR-mediated bicarbonate transport was significantly different between CF and control biliary organoids, with the former showing almost no transport before and after Kaftrio.
Further studies using other cystic fibrosis donor organoids and animal models of cystic fibrosis are needed to confirm these findings and better understand them, the team noted.
Taken together, these results highlight the “potential of Kaftrio to restore both chloride and bicarbonate secretion in the intestinal and biliary tracts of CF patients. [organoids]”, which is likely to counter “the hyper-acidification associated with bicarbonate deficiency not only in the intestine, but also in the bile ducts,” the researchers wrote.