Team led by FCT Researcher manages to increase efficacy of drug for cystic fibrosis

A team of researchers, led by FCT Investigator Paulo Matos, has identified a way to increase the efficacy of a cystic fibrosis drug up to seven times. By studying the mechanism of action of the drug Lumacaftor (about to be commercialized) within cells affected by the mutant protein that causes cystic fibrosis, the researchers identified specific targets for treatments of this debilitating disease. Their findings have been published in the prestigious journal Science Signalingmeriting a cover story.

Cystic fibrosis is a disease of the mucus and sweat glands, affecting mainly the function of the lungs, pancreas, liver, intestines, sinuses, and sexual organs. It is an inherited 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. About 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 percent 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 around the world have identified drugs that act as a "hair stick" for mutant CFTR proteins: they follow 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 sufficient 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 thorough experiments in human lung lining cells, Paulo Matos and his team were able not only 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 efficacy of the drug." He emphasizes, "The mechanism we describe in this study exists in other cells as well (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 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 of the University of Lisbon, funded by FCT. It was funded by FCT (Studentships de Doutoramento, Studentship de pós-doutoramento, Investigador FCT e projetos de I&D), and also by Gilead Genése, Portugal and the Instituto Nacional de Saúde, Dr. Ricardo Jorge.