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FCT Investigator leads study that increases efficacy of drug for cystic fibrosis


A team of researchers led by FCT Investigator Paulo Matos has uncovered a way to increase the efficacy of a drug for cystic fibrosis up to seven-fold. By studying the molecular mechanisms underlying how the drug Lumacaftor (soon to be released for therapy) acts inside cells affected by the mutant protein that causes cystic fibrosis, the researchers have identified specific cellular targets to improve treatment of this debilitating disease. Their findings were published in and made the cover of the journal Science Signaling.

Cystic fibrosis is a disease of the mucus and sweat glands that affects patients’ lungs, pancreas, liver, intestines, sinuses and sex organs. It is an inherited disease, caused by a mutation in a protein known as the CF transmembrane conductance regulator (CFTR). CFTR is a channel for chloride ions; it is inserted into the cell’s membrane, allowing chloride ions to flow into the cell and maintain crucial cellular function. Almost 2 000 mutations in the CFTR protein have been identified, causing defective or nonfunctional proteins. Although the most common mutation, which is found in more than 80% of patients, leads to a partially-functioning protein, the cells recognise it as defective and degrade it, before it gets to the cell membrane.

Over the years, researchers have identified several drugs that act as chaperones for these mutant CFTR proteins. The drugs support their processing in the cell and their insertion into the membrane. One of the most promising drugs is VX-809 (known as Lumacaftor). However, as Paulo Matos, explains “We and other had previously shown that this chaperoning effect may not be enough to rescue the presence and function of the mutant protein in the membrane, since it seems it is quickly removed from the membrane by another of the cell’s control mechanisms.”

Through a serious of very detailed experiments, in human cells that line the lung (epithelial cells), Paulo Matos and his team were able not only to circumvent this control mechanism – thus retaining CFTR in the membrane – but also, in this latest study, describe in detail the molecular mechanism underlying the drug’s effect. Paulo Matos is confident that, “Now that we know which molecular players are involved in the process, it should make it easier to selectively and safely improve the efficacy of the drug. Moreover, the mechanism we have described here acts in other cells, too (for example in certain types of cancer cells); therefore, understanding it may also have an impact on our understanding of the mechanisms underlying other diseases, and reveal a set of highly attractive new targets for rational drug design.”

Cláudia Loureiro (the first author of the study) and Paulo Matos, FCT Investigator BioISI – Biosystems & Integrative Sciences Institute (University of Lisbon)

This research was carried out by researchers from the Instituto Nacional de Saúde, Dr. Ricardo Jorge and FCT-funded BioISI – Biosystems & Integrative Sciences Institute of the University of Lisbon. It was funded by FCT (PhD Studentships, post-doctoral fellowships, FCT Investigator Grant, project grants), and also by Gilead Genése, Portugal and the Instituto Nacional de Saúde, Dr. Ricardo Jorge.