Team led by an FCT researcher succeeds in increasing the effectiveness of a drug for cystic fibrosis

A team of researchers, led by FCT researcher Paulo Matos, has identified a way to increase the effectiveness of a drug for cystic fibrosis by up to seven times. By studying the mechanism of action of the drug Lumacaftor (soon to be marketed) within cells affected by the mutant protein that causes cystic fibrosis, the researchers identified specific targets for treatments for this debilitating disease. Their results were published in the prestigious journal Science Signaling, earning them a cover story. 

Cystic fibrosis is a disease of the mucus and sweat glands, mainly affecting lung, pancreas, liver, intestine, sinus, and reproductive organ function. It is a hereditary disease caused by a mutation in a protein known as CF transmembrane conductance regulator (CFTR). CFTR is a chloride ion channel; when produced by the cell, it is inserted into its membrane, allowing the influx of chloride ions, which ensures essential cellular functions. Approximately 2,000 mutations in the CFTR protein have been identified, resulting in a defective or non-functional protein. Although the CFTR protein with the most common mutation (present in more than 80% of patients) still retains some function, cells recognize it as defective and degrade it before it is inserted into the membrane. 

Over the years, researchers around the world have identified drugs that act as "hairpins" for mutant CFTR proteins: they accompany the proteins in the cell, ensuring their insertion into the cell membrane. One of the most promising drugs is VX-809 (known as Lumacaftor). However, Paulo Matos points out a difficulty: "We and other groups have already shown that this 'hairpin' effect may not be sufficient to ensure the presence and function of the mutant protein in the membrane, since it appears to be removed from the membrane by another cellular control mechanism."

Through a series of meticulous experiments on human lung lining cells, Paulo Matos and his team managed not only to overcome this control mechanism—by retaining the function of the mutant CFTR—but also, in this study, to describe in detail the molecular mechanism underlying the drug's effect. Paulo Matos is confident: "Now that we know the molecular players in the process, it becomes easier to identify targets to selectively improve the drug's effectiveness." He emphasizes, “The mechanism we describe in this study also exists in other cells (for example, in certain cancer cells), which means that understanding it could facilitate the understanding of the mechanisms underlying other diseases and reveal a set of new targets for rational drug design.”

This work was carried out by researchers from the National Institute of Health, Dr. Ricardo Jorge, and the R&D Unit BioISI – Biosystems & Integrative Sciences Institute at the University of Lisbon, funded by FCT. It was funded by FCT (Studentships , Studentship , FCT Researcher, and R&D projects), as well as Gilead Genése, Portugal, and the National Institute of Health, Dr. Ricardo Jorge.