Pharmacological modulation of ion transport to treat the basic defect in cystic fibrosis and other genetic diseases
Cystic fibrosis (CF) is one of the most frequent genetic diseases, caused by mutations that impair the function of CFTR, a protein localized on the membrane of epithelial cells. The main role of CFTR is to mediate secretion of chloride and bicarbonate through the epithelia of different organs. This process controls the hydration and pH of the fluids covering epithelial surface. Loss of CFTR function has consequences in multiple organs including lungs, pancreas, liver, sweat glands, and the reproductive system. However, the lung disease is a 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. In many patients, the progressive loss of respiratory function in the last stage of the disease results into lung transplant as a life-saving intervention.
The 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. Such molecules act with different mechanisms. Correctors improve the stability and folding of CFTR when it is affected by mutations like F508del, the most frequent among CF patients. Instead, potentiators act as stimulators of CFTR and are therefore particularly effective for mutations that compromise the process of CFTR activation.
My research group has been particularly active in the search of 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 that are important as tools of research and possibly useful as drugs for other genetic diseases like polycystic kidney disease.
In collaboration with a research team led by Dr. Tiziano Bandiera at the Italian Institute of Technology (IIT), we are continuing our search for effective correctors and potentiators. The project is supported by the Italian Cystic Fibrosis Foundation. By screening thousands of molecules and chemical modification of the resulting hits, we have found so far correctors with very high potency and efficacy on bronchial epithelial cells from CF patients. The goal is to develop a promising preclinical drug candidate.
The basic defect in CF can be corrected by targeting other proteins. In 2008, my research group identified TMEM16A as a second type of protein that, in addition to CFTR, mediates chloride and bicarbonate secretion in epithelial cells. In theory, pharmacological stimulation of TMEM16A could circumvent defective CFTR, a strategy that could be important for those CF patients carrying mutation that are not sensitive to correctors and potentiators. We are now working on TMEM16A to confirm its importance as a therapeutic target in CF and to find pharmacological activators.
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