Nasal Potential Studies Utilizing Cystic Fibrosis Transmembrane Regulator (CFTR) Modulators
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of the study is to develop new biomarkers for studies of cystic fibrosis (CF).
      Defects in the gene encoding Cystic Fibrosis Transmembrane Regulator (CFTR) cause CF, an
      autosomal recessive disorder affecting mainly the pulmonary and digestive tract, leading to
      early death largely due to progressive loss of pulmonary function. In vitro experiments show
      that quercetin - a dietary supplement with a well-established safety profile for human use,
      including clinical trials in a variety of disorders encompassing cancer, heart disease, and
      as an anti-inflammatory agent - induces activation of CFTR. The nasal potential difference
      (NPD) test is a measurement of voltage across the nasal membrane and as a fundamental
      biomarker for CFTR activity in vivo. The NPD is a useful, well-established tool in CF
      research to determine both diagnoses as well as to measure the effect of new therapies. In
      vitro experiments show that quercetin induces activation of CFTR additive to that seen with
      current NPD reagents. In addition, it activates rescued mutant CFTR in vitro (∆F508 CFTR the
      most common cause of CF), whereas conventional agonists do not. Preliminary in vivo
      experiments mirrored these results and show that quercetin activates CFTR in human (n=12) NPD
      tests. Importantly, quercetin perfusion was well-tolerated by a validated sinus questionnaire
      and physician assessed nasal examination rating. These studies provide strong support for use
      of quercetin as potentiator of CFTR Cl- channel function by nasal administration. By adding
      quercetin to the sequence of perfusion solutions for NPD, the investigators may be better
      suited to detect ∆F508 CFTR activity of rescued mutant protein in the CF patient population.
    

Detailed description: 
      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.
    

Intervention name(s): quercetin
Intervention type(s): Other
Intervention description(s): health food supplement
Intervention MeSH terms: Quercetin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Cystic Fibrosis