Grant: Project Grant

Cystic fibrosis (CF), caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) protein, affecting >4400 individuals in Canada and >100,000 individuals worldwide. CF is characterized by a life-shortening multi-organ pathology of the respiratory system, GI tract, and reproductive organs. Recurrent lung infection with severe and uncontrolled inflammation is the major cause of morbidity and mortality in CF. The CF gene encodes the CFTR, a cell surface membrane protein that ensures ions and water secretion into the lung lumen. This mechanism is a prerequisite for the continuous clearance of infectious and toxic particles from the airways. Genetic mutations, however, prevent or severely impair the CFTR-dependent clearance of the lung and lead to chronic infection that culminate in the progressive destruction of the lung tissue. While nearly 90% of the mutations are approved for the highly efficient CFTR modulator combination therapy (Trikafta), mutations of the remaining 10% patients still lack effective pharmacotherapy. Furthermore, another 10-15% of CF patients cannot tolerate Trikafta or they are unresponsive to treatment. Thus, there is an unmet need to develop alternative therapy in CF. Here, we propose novel pharmacological and protein therapy approaches to alleviate the disease severity in patient populations that are not eligible for Trikafta or unresponsive to it. The pharmacological approach is based on our pilot studies that identified novel small molecules that stimulate the channel opening via a non-canonical mechanism and amplify the effect of the FDA-approved two potentiators. The second approach is based on the combination of i) genetically engineering the CFTR to be more functional, and ii) develop a novel vesicular delivery system that can target these CFTR proteins to airway cells that do not express drug-sensitive or any CFTR.