Nasal Potential Studies Utilizing CFTR Modulators (UAB Center for Clinical and Translational Science)

Flavonoids are a large group of naturally occurring polyphenolic compounds which are ubiquitous throughout the plant kingdom and are bio-available in fruits, vegetables, nuts, seeds, flowers, and bark. Quercetin has raised particular interest as it is not only a major component of the naturally occurring dietary flavonols, but it also seems to have anti-oxidant, anti-carcinogenic, anti-inflammatory, as well as cardioprotective functions. Recently, our laboratory and others have reported that quercetin, in addition to its other functions, plays a role in improving the function of chloride (Cl-) transport in the (CFTR). It is well established that genistein, a flavone related to quercetin, increases mutant and wild-type CFTR channel activity. Genistein is now widely used in various cell systems, tissues, and species as a robust CFTR activator. Although it has been extremely helpful in laboratory experiments, Genistein translates poorly into human experiments as it has poor dissolution in solvent. As almost all flavonoids activate CFTR, deeper examination of other members of this family is important for both clinical use as well as a tool for future clinical studies. Quercetin is now available in health food stores as a dietary supplement in both pill as well as beverage form. It may also be beneficial for the treatment of CF and for use as a direct activator of CFTR for use in clinical trials where measurements of CFTR activity are important. Through a better understanding of CFTR biogenesis and activation, new therapeutic approaches that restore activity to mutant CFTR molecules in vitro and in vivo are being developed. Biomarkers that can detect activity of rescued CFTR are required to measure therapeutic effects of new compounds. Current methods have yet to show consistent rescue of CFTR activity, raising the importance of optimizing detection strategies, including the most effective NPD endpoint. This may be particularly important for subjects harboring the ∆F508 mutation which in addition to its cell processing abnormality, also exhibits a channel gating defect (it does not activate with the conventional NPD agonist isoproterenol) thereby reducing detection of rescued protein. The investigators have previous experience evaluating alternative CFTR activating agents, both in CF animal models, and in human subjects. By adding quercetin to the sequence of perfusion solutions for NPD, the investigators may be better suited to detect CFTR activity of rescued mutant protein. In vitro experiments show that quercetin induces activation of CFTR additive to that seen with current NPD reagents. Preliminary in vivo experiments of non-CF individuals mirrored these results and show that quercetin activates CFTR in human NPD tests (n=12). Importantly, quercetin perfusion was well-tolerated by a validated sinus questionnaire and physician assessed nasal examination rating. As preliminary data suggest perfusion of quercetin may improve defective CFTR activation in surface localized ΔF508, use of this agent within an NPD protocol is likely to improve detection of ΔF508 CFTR resident at the cell surface, representing a potential means to identify new candidates for systemic CFTR potentiator therapies.