European Cystic Fibrosis Society

Page last updated 10 March 2010 

The 2010 Basic Science Conference will have 4 Special Groups Discussions (SGD) on 8 and 9 April 2010.
On each day 2 sessions will be held concurrently, therefore delegates will be requested to sign up for the session they wish to attend to assist in the planning. There is no additional charge to the registration fee.   

Thursday 8 April 2010 - 16:45-18:15

SGD I - Modulator insights into wt and F508del CFTR behaviour
Chairs: L. Galietta (IT) and I. Braakman (NL)

SGD II - CF biomarkers now and on the horizon
Chairs: C. De Boeck (BE) and J.P. Clancy (US) 

Friday 9 April 2010 - 18:00-19:30

SGD III - Alternate restorative strategies for CF
Chairs: F. Van Goor (US) and M. Mall (DE)

SGD IV - Inflammation in CF - getting to the routes by digging out the roots.
Chairs: A. Mehta (UK) and M. Chanson (CH)

SPECIAL GROUP DISCUSSION I
Modulator insights into wt and F508del CFTR behaviour
Chairs: L. Galietta (IT) and I. Braakman (NL)

Mutant CFTR is a druggable target.  In particular, the gating defect associated with class III mutations can be overcome with drug-like compounds called potentiators.  These compounds, also identified by high-throughput screening of large chemical libraries, enhance the activity of mutant CFTR channels to normal levels.  The trafficking defect caused by the deltaF508 mutation can be also ameliorated by small molecules called correctors.  However, deltaF508 correctors are typically more difficult to identify than potentiators and their efficacy is also smaller.  Furthermore, it is not clear whether correctors act by binding directly to CFTR or by modulating the activity and/or expression of other cell proteins.

This Discussion Group Session will address the following issues:
 
1) Do the correctors and potentiators work in any cell? Are the molecular mechanisms related to deltaF508 mistrafficking universal or cell type dependent?
2) Are the cell models used to study deltaF508 representative of the defect in vivo?
3) Why do all correctors rescue deltaF508 only to a maximum of 15%?  Does this tell us something about the defect or about the rescue?
4) How do we find out what is needed for increased rescue? 

SPECIAL GROUP DISCUSSION II
CF Biomarkers Now and on the Horizon
Chairs: JP Clancy (US) and Kris De Boeck (BE)

Currently available CF therapies target symptoms that result from CFTR dysfunction, and their systematic application has lead to steady improvements in CF patient longevity and quality of life.  Novel strategies that target mutant CFTR proteins (ie: CFTR modulators) and restore CFTR function are currently in a number of clinical trials, and their use requires the development of novel CFTR biomarkers to detect biologic effects and to link their mechanism of action to clinical outcome measures.  Currently, there are only two CFTR biomarkers that have frequently been used in multi-center clinical trials of CFTR modulators, including sweat chloride [Cl-] measurements and the nasal potential difference measurement (NPDs). 
The sweat [Cl-] is an indirect measure of CFTR activity in that it relies on retained activity of the epithelial sodium channel (ENaC) for Cl- transport through CFTR.  It is an attractive biomarker, however, due to it’s lack of CF tissue pathology and thus potentially high sensitivity to detect CFTR effects. 
The NPD is capable of isolating CFTR-dependent Cl- transport independent of ENaC and CFTR regulation is similar compared with the lower airway, but typically demonstrates a lower signal/noise ratio than sweat [Cl-] measures, and is technically more demanding for study subjects and operators. 
Both of these CFTR biomarkers are undergoing optimization for use in clinical trials, including the development of standard operating procedures (SOPs) for assay conduct, hands-on training sessions, development of sequential qualification steps for operators, and centralized over-read/interpretation of data.  The results from recently conducted Phase II trials of CFTR modulators (eg: PTC124, VX-770, VX-809) indicate that both assays are capable of detecting biologic effects of modulators in vivo, but their capacity to detect bioactivity has varied across studies depending on the nature of the modulating strategy, study sites, and the specifics of assay conduct.  In addition, the relationship between restored CFTR activity as measured by sweat [Cl-] and the NPD compared with clinical outcome measures remains unclear. 
In this Small Group Discussion, recent developments in the use of these assays in CFTR modulator trials will be discussed, identifying areas for research and optimization.  In addition, experience with new and novel CFTR biomarkers will be presented and discussed by SGD participants, including GI outcome measures (Intestinal Current Measurements – ICM, biochemical detection of CFTR, and real time RT-PCR quantification of CFTR transcript levels in rectal biopsies), detection and localization of CFTR by immunostaining in patient samples, emerging imaging modalities, and potential markers of CFTR expression and activity in blood samples.  It is clear that continued identification, characterization, and standardization of new CFTR biomarkers is needed.  Defining the relationships between CFTR biomarkers and clinical outcome measures will enhance the conduct of CFTR modulator clinical trials, and accelerate bringing new therapies to CF patients.

SPECIAL GROUP DISCUSSION III:
Alternate restorative strategies for CF
Chairs: F. Van Goor (US) and M. Mall (DE)

Although tremendous progress has been made in the development of small molecule compounds that correct and/or potentiate mutant CFTR function, it is currently not known whether this pharmacological approach will improve CFTR function sufficiently to result in an effective therapy of CF organ disease. Therefore, the aim of this session is to discuss alternative strategies to restore/circumvent CFTR malfunction on the cellular and whole organ level in the airways as well as in other organ systems.

Specifically, this Special Group Discussion will focus on the following issues:

1. Alternative pharmacological strategies to restore the ion and fluid transport defects in CF.
•  What is the current progress in the pre-clinical and clinical development of ENaC blockers and alternative Cl- channel modulators?
•  How would combinations of CFTR-modulators and alternative ion transport strategies impact clinical efficacy?

2. Current targets and approaches for regenerative cell-based therapies, such as embryonic stem cells (ES) and inducible pluripotent stem cells (iPS)

3. Will alternative ion transport pathways and restorative cell-based therapies compensate for the pleiotropic consequences of mutations in the CFTR gene?

4. Based on the current knowledge, what should be future directions of basic and clinical research?

SPECIAL GROUP DISCUSSION IV:
Inflammation in CF – getting to the routes by digging out the roots
Chairs: A. Mehta (UK) and M. Chanson (CH)

Clinicians find it difficult to manage CF inflammation- either infection-induced deterioration of the lung, or decline in the absence of cultured pathogens. Clinical practice might well differ if the excessive inflammatory response, which is a hallmark of CF, might be partly independent of infection. Hence the inflammation discussion will begin with a clinical view from Stuart Elborn.

Hypothesis: A hyper-inflammatory state has been postulated to play a role in the pathogenesis of CF airway disease. A polemic issue has been whether it is the absence of wt-CFTR, or presence of a dysfunctional CFTR that triggers dysregulated inflammatory pathways affecting the production of proteo-lipid (chemokines, cytokines eiocosanoids) mediators. Since the origins and mechanisms underpinning CF inflammation are disputed. A major aim of this discussion is to clarify the degree to which inflammation occurs as a result of the following processes:

1) Is localization of CFTR in the plasma membrane required for basal or stimulated inflammatory mediator production?
2) Does CFTR absence or dysfunction trigger other defects in the production of inflammatory mediators?
3) What are the potential hubs (eicosanoid pathway, NF-B pathway, oxidative stress/mitochondrial dysfunction) in the CFTR interactome?
4) Are available animal and cell models of CF capable of yielding clues to the above?

Objective 1: Getting the roots right.
ROOT 1, because both wild type (say 75%) and F508del CFTR (say 90%) are degraded, how much excess inflammation occurs when CFTR is missing? One consequence is the question whether the missing/disturbed regulation occurs because the residual (undegraded) 25% of wild type is the element that is missing in F508del cells to leave only 5% of mutant CFTR in cell.

ROOT 2, is CF inflammation a knock-in disease where the residual F508del (say 5% left over) has one or more positive function(s) of a magnitude sufficient to induce disease? The assumption here is that F508del in this setting exerts its heterozygote advantage even when allied to a wild type CFTR and exhibits its disease propensity when allied to another copy of the same defect in half the CF patients in Northern Europe. Clearly, all roots cause processes knock-out and knock-in could be operant together.

Objective 2: Getting the routes right.
This session will promote an open discussion to foster future research on the inflammatory response of CF airway epithelial cells. For example:
• Are epithelial cells the only target of CFTR dysfunction(s) and source(s) of inflammation?
• What about CFTR in leukocytes, endothelial cells and immune cells. The assumption is that altered responses of these cells, together with defective CFTR chloride channel function in epithelial cells, may contribute to various degrees to the CF airway phenotype.