Monday, April 28, 2025
4/28/2025
A novel mechanism based therapy for cystic fibrosis - Approximately 70,000 individuals worldwide suffer from cystic fibrosis (CF), a debilitating ion transport disease characterized by abnormal mucus secretion (primarily involving the lungs). Following years of symptom management as the only treatment option, Kalydeco (ivacaftor or VX-770), and Orkambi, a combination of ivacaftor plus lumacaftor (VX-809) were approved by the FDA to treat the underlying cause of CF. Because ivacaftor alone is approved for only ~4-5% of CF patients and ivacaftor/lumacaftor, while approved for nearly half of CF patients, improves lung function to a lesser degree than ivacaftor does in the other subset of patients, new drugs addressing the root cause of CF in a majority of patients are needed. CF patients harbor mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which localizes to the cell membrane and controls salt transport and, thus, water flow. Such mutations decrease the amount and/or function of CFTR, leading to CF pathologies. The most widespread of several CF mutations (75% worldwide) is the deletion ¿F508, which causes improper folding of CFTR. As a result, CFTR is degraded before it can reach the membrane, where it must be functional. Small molecules called correctors (e.g., VX-809) work by promoting trafficking of mutant CFTR to the cell surface. Because existing CF treatments are limited, efforts are warranted to target other mechanisms of increasing the levels, trafficking, and/or functionality of CFTR¿F508 to develop novel drugs for single or conjoint use to treat CF. The ERAD pathway of the ubiquitin signaling system has been exploited to yield inhibitors of gp78, a major ERAD ligase that degrades misfolded CFTR; such inhibitors are predicted to increase membrane levels of mutant but still active CFTR, providing therapeutic benefit. In the course of this work, a new mechanism for CFTR preservation not due to direct inhibition of gp78 was uncovered. A class of false positives in the gp78 inhibitor screen are able to stabilize CFTR, apparently by inhibiting ubiquitin-binding UBA domains, leading to blocked CFTR degradation and increased levels of CFTR, which could increase the amount of CFTR at the cell surface, especially in combination with correctors such as VX-809. Initial proof of concept for this model has been obtained. Accordingly, in the proposed studies a FRET-based assay for UBA domain inhibitors will be employed to screen for compounds that target UBA domains, and positives will be tested for potency and selectivity. Inhibitors from this screen are expected to increase levels of functional CFTR, improving the regulation of mucus in the lungs of CF patients; selected compounds will therefore be evaluated for proof of concept in biochemical and cell-based models of cystic fibrosis.
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