Treatment with the CFTR modulators elexacaftor, tezacaftor and ivacaftor improves the innate defenses in the nasal mucosa and reduces inflammatory reactions in children with cystic fibrosis. This was shown by researchers at the Charité - Universitätsmedizin Berlin in a study funded by Mukoviszidose e.V. using epithelial and immune cells from the upper respiratory tract.
The triple therapy with the CFTR modulators elexacaftor, tezacaftor and ivacaftor for patients with cystic fibrosis (CF), which will also be approved in Europe in 2020, is effective and safe. This has now been confirmed by long-term studies of up to three years. It is also now known that the function of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) ion channel, which is affected by CF, recovers under treatment. Researchers at the Charité - Universitätsmedizin Berlin have now shown in single cells from the nasal mucosa of children with CF aged 6 to 11 years that the inflammatory reactions of the immune cells in the upper respiratory tract decrease under triple therapy and that the innate defenses also recover.
The results underline the potential of CFTR modulators to stop the vicious cycle of infection, inflammation and progressive lung damage in CF and to restore epithelial homeostasis and immune defense, especially if treatment is started early, according to Dr. Saskia Trump who led the study together with Dr. Simon Gräber and Prof. Marcus Mall.
The epithelium is the uppermost cell layer of the mucosa and plays a crucial role in maintaining a stable internal environment in the body, known as homeostasis. It serves as a barrier that regulates which substances enter the body.
The research team investigated which genes were active in immune and epithelial cells from the nasal mucosa of children. They analyzed the cell samples once at the beginning and after the triple therapy and compared them with samples from the nasal mucosa of healthy children. They used single-cell transcriptomics, which allowed them to measure the activity of thousands of genes simultaneously.
According to Trump and her colleagues, further studies are now needed that include CF patients of different ages and with different stages of lung disease. Among other things, the researchers want to determine whether the triple therapy also has a positive effect on the cells of the upper airways in older patients with more severe lung disease.
Original publication: Loske J, Völler M, Lukassen S, et al. Pharmacological improvement of CFTR function rescues airway epithelial homeostasis and host defense in children with cystic fibrosis. Am J Respir Crit Care Med. Published online January 23, 2024.
doi: 10.1164/rccm.202310-1836OC
Viscous mucus due to genetically modified ion channel
In cystic fibrosis, the gene for an ion channel on the surface of cells is altered. The affected ion channel is called cystic fibrosis transmembrane conductance regulator (CFTR). More than 2,000 different genetic changes, or mutations, in the CFTR gene are known. Normally, the channel transports chloride ions out of the cell. In cystic fibrosis, the channel is either unable to do this, or only able to do so to a limited extent, which means that more water remains in the cells and the cell surfaces dry out. This leads to the formation of thick mucus that clogs the airways of the lungs and internal organs such as the intestines. The disease is also characterized by an increased salt content in the sweat.
Recently developed small-molecule CFTR modulators can treat certain causes of cystic fibrosis, including the F508del CFTR mutation, which is present in about 90 percent of patients. These modulators activate existing channels and help the CFTR channel to be produced correctly.
