Nasal Potential Studies Utilizing Cystic Fibrosis Transmembrane Regulator (CFTR) Modulators

January 27, 2012 updated by: Dr. Steven M Rowe, University of Alabama at Birmingham

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

32

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 8-65 years old
  • absence of pulmonary exacerbation in the last 2 weeks
  • willingness to perform nasal potential difference measurement

Exclusion Criteria:

  • Need for chronic oxygen supplementation
  • positive for B. cepecia within the last year
  • active participation in another interventional trial utilizing ion transport modulators
  • interfering medical conditions
  • pregnant females

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: quercetin
health food supplement
health food supplement

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
NPD Biomarker
Time Frame: patients enroll for a single 2-4 hour visit
Determine whether the NPD biomarker can be improved by including the potentiator quercetin to activate CFTR dependent ion channel activity among CF individuals with surface localized CFTR mutations
patients enroll for a single 2-4 hour visit

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Residual CFTR activity
Time Frame: patients enroll for a single 2-4 hour visit
Determine the relationship between quercetin induced residual CFTR activity (detected in CF patients by the NPD biomarker) and stimulated short circuit currents (Isc) in primary airway cultures harvested from CF tissue donors.
patients enroll for a single 2-4 hour visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2010

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

November 1, 2011

Study Registration Dates

First Submitted

June 1, 2010

First Submitted That Met QC Criteria

May 4, 2011

First Posted (Estimate)

May 5, 2011

Study Record Updates

Last Update Posted (Estimate)

January 31, 2012

Last Update Submitted That Met QC Criteria

January 27, 2012

Last Verified

January 1, 2012

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Cystic Fibrosis

Clinical Trials on quercetin

3
Subscribe