In patients with a common form of cystic fibrosis, a new causative triple therapy improves impaired ion channel function in the airways and intestines. This is what scientists at the German Center for Lung Research (DZL) and Charité - Universitätsmedizin Berlin have discovered.
"The triple therapy restores the function of the ion channel, which was previously around 0 to 10 percent in the studied patients, to about 50 percent of the activity of a healthy channel." said Dr. Simon Gräber, a physician and researcher at the Department of Pediatrics with a focus on pneumology, immunology and intensive care medicine at Charité - Universitätsmedizin Berlin and one of the study's first authors. It is known from another form of cystic fibrosis, where ion channels still work around 50 percent in untreated patients, that the disease runs mildly in the long term. Therefore, "this result is especially important for the long-term prognosis of patients."
Newly developed modulators address the cause of the disease
In cystic fibrosis (CF), the gene for an ion channel on the cell surface is altered. The ion channel affected is called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). More than 2,000 different genetic alterations, i.e. mutations, in the CFTR gene are known. Normally, the channel transports chloride ions out of the cell. In cystic fibrosis, it either cannot do this at all or only to a limited extent, which is why more water remains in the cells and the cell surfaces dry out. This results in the formation of a viscous mucus that clogs the airways of the lungs and internal organs such as the intestines. Another characteristic of the disease is an increased salt content in sweat.
Recently developed so-called small molecule CFTR modulators make it possible to treat certain causes of cystic fibrosis, including the F508del CFTR mutation, which is present in a good 90 percent of all patients. These modulators activate existing channels and help ensure that the CFTR channel is properly established. Previous clinical studies have already shown how well the triple combination of the new drugs affects patients' lung function and quality of life. Evidence that the ion channel in the airways and intestines works again and to what extent the malfunction can be corrected has been lacking until now.
Clear treatment effects
Three DZL centers and the Charité Cystic Fibrosis Center participated in the functional analysis of the triple therapy. In total, the scientists studied 107 cystic fibrosis patients. In 55 of the study participants, one of the two copies of the ion channel gene was affected by the F508del-CFTR mutation, while the other gene had a so-called mutation with minimal function. All other study participants carried the F508del-CFTR mutation in both copies of the channel gene.
To assess how well the CFTR channel was functioning, the researchers determined the salt concentration in the patients' sweat, used nasal potential difference (NPD) and intestinal current measurement (ICM). They used these to examine the patients once before and eight to sixteen weeks after they started the triple therapy.
In patients who had not previously received CFTR modulators, channel function increased from zero to 50 percent. Some of the patients were already taking two of the modulators, raising channel function to about ten to twenty percent already. "In both groups, the improvement in CFTR channel function led to a significant and noticeable improvement in lung function for those affected," says Professor Marcus Mall, head of the study and director of the Clinic for Pediatrics with a focus on pneumology, immunology and intensive care medicine at Charité.
Long-term studies needed
However, the researchers could only see a weak connection between the increased channel function and the short-term improvement in clinical values, such as lung function. They suspect that this is because lung function depends on many other factors, for example chronic changes in the airways. Moreover, they recorded these parameters only for a short period of time. Therefore, they claim that long-term studies are essential to determine whether the extent of improvement in ion channel function can predict the further course of the disease in individual patients. Ten percent of cystic fibrosis patients cannot yet be helped with the modulators of triple therapy because they have other mutations. Dr. Gräber and his colleagues are currently conducting intensive research into new treatments for this small group as well.
Original publication: Graeber SY, Vitzthum C, Pallenberg ST, et al. Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508delAlleles [published online ahead of print, 2021 Dec 22]. Am J Respir Crit Care Med. 2021;10.1164/rccm.202110-2249OC. doi:10.1164/rccm.202110-2249OC.
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