The European Project “New therapeutic approaches for the treatment of cystic fibrosis based on small molecules transmembrane anion transporters ” concludes

As part of the Horizon 2020 program, Research and Innovation Actions (RIA), a project was developed to develop a new approach for the treatment of cystic fibrosis (CF). The clinical picture of the CF patient is the consequence of the malfunctioning of the CFTR protein which prevents the transport of chloride and bicarbonate through the epithelial membranes. Therefore, the care of the CF necessarily passes from the correction of this defect. The problem lies in the variety of mutations that affect the gene encoding the CFTR. Consequently, a great effort was made in identifying molecules capable of interacting with defective CFTR and correcting it. This approach necessarily requires the development of specific drugs for each class of CFTR defects. The idea in this project was to use small organic molecules, called anionophores, capable of transporting chloride and bicarbonate through cell membranes, in order to compensate for the deficiency of the defective CFTR protein in CF patients.

The idea of a functional replacement of the defective protein using anionophores should be a strategy that allows the use of a single drug to correct the basic defect, regardless of the mutation affecting the CFTR. The objective is to identify substances capable of transporting chloride and bicarbonate on the cells of CF patients, in order to replace the defective function of CFTR. The project Novel therapeutic approaches for the treatment of cystic fibrosis based on small molecule transmembrane anion transporters, TAT-CF (Horizon 2020 research and innovation program under grant agreement No. 667079) was funded with over 4.5 million euro, and was carried carried out by 8 research groups from 5 countries, coordinated by Prof. Roberto Quesada of the Department of Organic Chemistry of the University of Burgos.

Two groups (University of Burgos, Spain and the company Avidin, Hungary) have undertaken a synthesis program of new compounds with the capacity to transport chloride and bicarbonate through the membranes. More than 300 compounds were subsequently tested in cells, to identify the most effective, by the group of the U.O.C. Medical Genetics of the Ist. Gaslini (Italy). The potentially useful substances were analysed in detail to identify their molecular transport mechanism by the group of the Institute of Biophysics, CNR (Genoa, Italy), while the impact on the physiology of cells and on the properties of the pericilliar fluid and mucus were studied by the groups of the group of the Institute of Biophysics, CNR and Ist. Gaslini ; transport measurements were facilitated by the development of new probes to quantify chloride and intracellular bicarbonate by the company Steinbeis Innovation (Germany). On the other hand, the most interesting substances were studied with the criteria of medicinal chemistry from the company Avidin, while the pharmacological kinetic properties and the most appropriate pharmaceutical formulations have been examined by the company Bioneer Pharma (Denmark) and by the development group of pharmaceutical industry Biopraxis Research (Spain). The project included the preclinical study, both in model systems based on patients cells and in animal models, by the Development and Regeneration Programs of the Consejo Superior de Investigaciones Cientificas (CSIC, Spain), Biopraxis Research, Bioneer Pharma.

This project has examined a totally innovative proposal that has never been explored before. Substances with good transport activity have been identified, and patent applications have been submitted for the most promising substances. At the end of the European Union-funded project, a series of potential molecules were prepared ready for clinical trials aimed at CF therapy. The collaboration between academic groups, that synthesise the substances and study the basic properties of anionophores, with groups in the pharmaceutical industry, experts in drug formulation and medicinal chemistry, has guaranteed the success of the project. Therefore, this innovative multidisciplinary study opens up new horizons in the treatment of the basic defect of cystic fibrosis, with the added value of being designed to recover the transport of anions, chloride and bicarbonate, in cells, regardless of the disease-causing mutation.

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