Pharmacological modulation of ion transport to treat the basic defect in cystic fibrosis

Cystic fibrosis (CF), one of the most frequent genetic diseases, is caused by loss of function of CFTR, a membrane protein that mediates chloride and bicarbonate transport in the epithelia of different organs.  Loss of CFTR function affects multiple organs but resultant lung disease is the major cause of morbidity and mortality in CF.  The lack of CFTR impairs the innate natural defenses of the airways causing bacterial infection and mucus accumulation.
This basic defect in CF can be targeted with pharmacological strategies.  Depending on the type of mutations, CFTR activity can be restored with specific drugs called correctors and potentiators. 
My research group has been particularly active in the search for effective correctors and potentiators to treat the basic defect in CF.  In collaboration with Prof. Alan S. Verkman (University of California San Francisco) we developed high-throughput methods that were subsequently used to screen large chemical libraries.  With this strategy, several active molecules were found.  High-throughput screening also allowed identification of potent and selective CFTR inhibitors (e.g. CFTRinh-172) that are important as tools of research.
I also collaborated with a research team led by Dr. Tiziano Bandiera at the Italian Institute of Technology (IIT) to find novel CFTR correctors.  The project, supported by the Italian Cystic Fibrosis Foundation (FFC), led to the discovery of the corrector ARN23765,endowed with picomolar potency.
The basic defect in CF can be potentially corrected by targeting other proteins. This is particularly important for CF patients who carry “undruggable” mutations, i.e. insensitive to potentiators and correctors.  We focus on two proteins: TMEM16A, a second type of  chloride channel, and ATP12A, a proton pump. Pharmacological activation of TMEM16A could overcome defective anion secretion in CF. While pharmacological inhibition of ATP12A could prevent the acidification that occurs in CF airways.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.