Team led by an FCT researcher manages to increase 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 (about to be marketed) within cells affected by the mutant protein that causes cystic fibrosis, the researchers have identified specific targets for treatments of this debilitating disease. Their results were published in the prestigious journal Science Signalingwith a cover story.

Cystic fibrosis is a disease of the mucus and sweat glands, mainly affecting the function of the lungs, pancreas, liver, intestines, sinuses and sexual organs. It is a hereditary disease caused by a mutation in the 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. Around 2,000 mutations in the CFTR protein have already been identified, resulting in a defective or non-functional protein. Although the CFTR protein with the most frequent mutation (present in more than 80% of patients) still retains some function, the cells recognize it as defective and degrade it before it is inserted into the membrane.

Over the years, researchers from all over the world have identified drugs that act as "hair sticks" for mutant CFTR proteins: they accompany the proteins into 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 'hair stick' effect may not be enough to ensure the presence and function of the mutant protein in the membrane, since it seems to be removed from the membrane by another cellular control mechanism."

Through a series of detailed experiments on human lung lining cells, Paulo Matos and his team not only managed to overcome this control mechanism - 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 efficacy." "The mechanism we described in this study exists in other cells too (for example, in certain cancer cells), which means that understanding it could make it easier to understand the mechanisms underlying other diseases, and reveal a number of new targets for rational drug design."

This work was carried out by researchers from the Instituto Nacional de Saúde, Dr. Ricardo Jorge and the R&D Unit BioISI - Biosystems & Integrative Sciences Institute of the University of Lisbon, funded by FCT. It received funding from the FCTStudentships DoctoralStudentships , Postdoctoral Studentship , FCT Investigator and R&D projects), as well as from Gilead Genése, Portugal and the Dr. Ricardo Jorge National Health Institute.