European Cystic Fibrosis Society

2011 ECFS Basic Science Conference
March 30 – April 2, 2011 – Tirrenia, ITALY

Author: Luis Galietta

In the last years, the ECFS Basic Science Conference has become an appealing meeting, particularly for young investigators who have the opportunity to present their data and interact with experts in the cystic fibrosis field.  The size of the conference, with a little more than 100 attendants from European and North American countries, is adequate for very fruitful discussions.

This year the conference was chaired by Christine Bear (Hospital for Sick Children, Toronto, Canada), Harry Cuppens (KULeuven, Leuven, Belgium), and Luis Galietta (Istituto Giannina Gaslini, Genova, ITALY).  As in previous years, the conference was organized as two key-note lectures, nine symposia, and four special group discussions.  The aim was to cover, as much as possible, all fields of the basic research on cystic fibrosis pathogenesis and novel therapeutic strategies, with a particular attention to topics which had not been touched in previous conferences.  Each symposium included presentations from invited speakers and from 2-3 young investigators selected among submitted abstracts.
The first key-note speaker was Bat-Sheva Kerem (Hebrew University, Jerusalem, Israel) who talked about the molecular mechanisms that affect the efficacy of pharmacological agents for nonsense mutations.  These drugs, such as PTC-124, allow the read-through of premature stop codons and therefore the synthesis of a full length CFTR protein.  However, a variable response was found among cystic fibrosis patients with such mutations.  It appears that the limiting factor affecting the response to PTC-124 is the abundance of CFTR mRNA. Indeed, the process of nonsense-mediated mRNA decay (NMD), which is particularly active in some patients, significantly reduces the CFTR transcript. On the other hand, the presence of truncated CFTR proteins in the endoplasmic reticulum activates the unfolded protein response (UPR) that in turn affects the NMD.  Bat-Sheva Kerem’s results indicate that the interplay between NMD and UPR has important consequences on the response to read-through drugs.

The second key-note speaker, Jeffrey J. Wine (Stanford University, USA), talked about submucosal glands and their involvement in the genesis of cystic fibrosis lung disease.  In addition to the surface epithelium, submucosal glands of the airways are also affected by the lack of CFTR function.  Defective anion/fluid secretion in the gland lumen impairs the delivery of mucins and antimicrobial molecules to the airway surface.  Prof. Wine compared the properties of glands from four different species and their regulation by cAMP- and calcium-dependent signaling.  Besides human and murine samples, it is now possible to study glands from cystic fibrosis pigs and ferrets.  These two new animal models greatly enhance the possibilities to study cystic fibrosis lung disease at different stages, from birth to adult life. 

The nine symposia covered several different topics including CFTR structure, pharmacological correction of basic defect, identification of alternative drug targets, epithelial physiology, infection, inflammation, modifier genes, and animal models.

Investigation of the abnormalities in CFTR protein folding and maturation caused by CF mutations, particularly by F508del, and the possibility of correction with small molecules were the main topics of the first two symposia.  The F508del mutation impacts CFTR protein at multiple levels, including NBD1 folding, when the protein is still being synthesized, and subsequent domain-domain interactions.  Correction of these defects with small molecules appears as a very tough task, with compounds identified by high-throughput screening of large chemical libraries being quite effective in cell lines but much less active in primary cells.

Other two symposia were dedicated to the investigation of other ion transport systems expressed in epithelial cells and their relationship with cystic fibrosis pathogenesis.  There were presentations on calcium-activated chloride channels, the epithelial sodium channel ENaC, the anion transporters of the SLC26 family, and the regulation of ion transport by different autocrine and paracrine mechanisms. These studies are important to develop novel strategies to overcome the ion transport defect in cystic fibrosis. For example, ENaC activity appears to be regulated by soluble molecules in the airway surface liquid.  In particular, proteases activate ENaC and therefore increase sodium/fluid absorption.  This activity is counteracted by protease inhibitors such SPLUNC1.  Inhibition of ENaC cleavage by pharmacological protease inhibitors may be a way to improve airway surface hydration and mucociliary clearance.  Another strategy could be to stimulate alternative chloride channels.  The TMEM16A protein appears as an interesting target for this approach.

Symposia 5 and 6 were instead devoted to inflammatory mechanisms in cystic fibrosis and host-pathogen interactions.  Various studies performed in cystic fibrosis mice and in cell lines have indicated the possibility of a direct link between CFTR defective activity and/or mistrafficking and inflammation.  For example, pharmacological inhibition of CFTR-dependent ion transport appears to reproduce the effect of mutations by enhancing the production of soluble mediators of inflammation.  Pharmacological modulation of pro-inflammatory mechanisms may be a way to stop or slow down the progression of the lung pathology in cystic fibrosis.

Very important information related to cystic fibrosis pathogenesis may arise from the study of novel animal models such cystic fibrosis pigs and ferrets.  Symposium 7 was dedicated to this topic.   In particular, one presentation dealt with the recently developed F508del-CFTR pig.  It was particularly interesting to hear that the behavior of F508del-CFTR protein in these animals reproduces what has been described so far in human cells, in terms of mistrafficking and residual function.  Furthermore, F508del pigs show a severe disease resembling cystic fibrosis in humans.
The remaining symposia were dedicated to the identification of genes with the ability to modify the severity of cystic fibrosis in different organs and the development and testing of therapeutic strategies to restore normal ion transport in cystic fibrosis patients.  There were presentations reporting the results of very large association studies, involving thousands of cystic fibrosis  patients, to detect genes with the ability to modify the lung disease or the intestinal phenotype.  In particular, a modifier of lung disease in patients with F508del mutation was detected in the 11p13 region.

As in previous years, the attendance of young investigators was strongly supported by grants from various organizations.  This year the sponsors were Vertex and the Italian Foundation for Cystic Fibrosis (FFC), with support from the Italian Society for Cystic Fibrosis (SIFC) and the UK CF Trust.

Award Winners

Young Fellows Travel Award:
Alexandre Hinzpeter, FR
Ramona Marrapodi, IT

Student Helper Award:
Abdel Aissat, FR
Ambra Gianotti, IT
Stefania Monterisi, IT
Liam O’Ryan, UK
Vinciane Saint-Criq, IE
Kendra Tosoni, IT

Free Registration Young Researchers:
Supported by FFC
Eugenio Fernandez Alanis, IT
Lauretta Galeno, IT
Nicola Ivan Lorè, IT
Davide Losa, CH
Carlotta Marasini, IT

UK CF Trust Young Investigator Travel Award:
Natasha Cant, UK
Guy Hughes, UK
Tracy Rimington, UK
Helen Wallace, UK

SIFC Young Investigator Bursary
Valentina Paracchini, IT
Paolo Scudieri, IT