Trial Information

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.