Kaftrio Rescues Chloride, Bicarbonate Deficits in GI Tissues
The triple combination therapy Kaftrio restores the function of CFTR — the defective protein in cystic fibrosis (CF) — and associated chloride and bicarbonate flow in gastrointestinal “mini-organs” derived from a patient carrying the most common CF-causing mutation, a study shows.
These findings highlight the benefits of Vertex Pharmaceuticals’ Kaftrio, sold as Trikafta in the U.S., beyond the most well-studied chloride flow. They suggest it also may help counter the abnormally acidic environment resulting from the loss of CFTR-dependent bicarbonate secretion that contributes to thick mucus obstruction and inflammation.
The study, “Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers,” was published in the Journal of Cystic Fibrosis.
CF is caused by a faulty CFTR, a channel protein that normally controls the flow of water and ions through cells, due to mutations in the CFTR gene. CFTR deficiency leads to the accumulation of thick and sticky mucus that clogs the airways and digestive tract.
While this is due to deficient transport of two important ions, chloride and bicarbonate, most studies have focused on the restoration of chloride flow alone.
Notably, bicarbonate is necessary to maintain a proper pH, or acid-alkaline, balance on the cell surface, and low levels were shown to increase organ acidity (lower pH) and alter mucus properties. This promotes thick mucus production and obstruction, and increases susceptibility to bacterial infections.
Now, a team of researchers in the Netherlands evaluated whether the approved CF therapy Kaftrio restored chloride and bicarbonate transport in gastrointestinal organoids derived from a CF patient carrying F508del, the most common CF-causing mutation.
Kaftrio combines three CF oral medicines: elexacaftor and tezacaftor — designed to help faulty CFTR get to the cell membrane by correcting its structural deficit — and ivacaftor, a so-called CFTR potentiator that aims to open blocked channels allowing water and ion transport.
In Europe, it is approved for CF patients with at least one F508del mutation, also known as Phe508del, while in the U.S. its label was expanded to patients with other specific mutations.
Patient-derived organoids are 3D “mini-organs” that better mimic diseased tissue, and are considered of value in predicting a therapy’s clinical benefit. The researchers developed organoids of the intestine and of cholangiocytes, the cells that line bile ducts — tube-like structures in the liver that carry bile to the small intestine to aid in digestion.
Organoids from a healthy donor also were developed as controls.
Results showed that Kaftrio significantly increased both CFTR-mediated chloride and bicarbonate transport in CF patient-derived intestinal organoids, reaching 50% of the response observed in control organoids.
Treatment also resulted in a similar chloride over bicarbonate transport ratio as observed with the healthy CFTR protein and comparable with that previously reported for lab-grown CF lung models.
These findings suggest that Kaftrio changes the conformation of the F508del-CFTR protein “such that its ion selectivity closely mimics that of the [healthy] channel,” the researchers wrote.
In CF biliary organoids, Kaftrio significantly increased CFTR-mediated chloride transport, but not that of bicarbonate.
Further analyses showed that, in contrast to intestinal cells, cholangiocytes displayed CFTR-independent chloride and bicarbonate transport that was mediated by calcium-dependent chloride channels.
Cholangiocytes were found to secrete bicarbonate mainly through AE2, a chloride-bicarbonate exchanger protein, that is facilitated by CFTR-mediated chloride transport.
“This model implies that restoration of Phe508del-CFTR-mediated chloride secretion suffices to restore biliary bicarbonate secretion,” the team wrote.
Notably, CFTR-mediated bicarbonate transport was significantly different between CF and control biliary organoids, with the former showing nearly no transport before and after Kaftrio.
More studies using additional CF donor organoids and animal models of CF are needed to confirm these results and better understand them, the team noted.
Overall, these findings highlight Kaftrio’s “potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary [organoids],” which is likely to counter bicarbonate deficiency-associated “hyper-acidification not only in the intestine, but also in the biliary tract,” the researchers wrote.