Isabelle Sermet-Gaudelus is MD, PhD, Professor of Pediatrics and head of the Pediatric Cystic Fibrosis Center. Hopital Necker-Enfants Malades, which is one of the biggest in Europe. She is presently the co-director with A Edelman of Team 2/INSERM U 1151: Epithelial channellopathies, Cystic Fibrosis and other diseases. Her translational research is based on phenotype-genotype studies for Cystic Fibrosis using different epithelial electrophysiological measurements and biochemical tests both in vivo and in tissues derived from patients . Basic research focuses on impact of selected interacting proteins on CFTR (dys)function and identification of partner proteins as novel targets for therapies.

Aleksander Edelman, CNRS Research Director (DR1), Head of the team 2 (Epithelial Channel diseases: cystic fibrosis and other diseases) at INSERM U1151, Paris France. Aleksander Edelman is an expert in epithelial physiology, proteomics and protein biochemistry. The team he is managing investigates the mechanisms underlying protein misfolded diseases (PMDs), such as cystic fibrosis and alpha 1 ant-trypsin deficiency focusing on protein-protein interactions, gene regulation, inflammation and ion transport. The final aim of AE research is to unmask novel targets for PMDs. Aleksander Edelman is the scientific director of proteomic core facility at Necker site in Paris.

Focus

We investigate misfolded protein biogenesis and correction, taking the CFTR protein as a model. We focus on the role of intermediary filaments in assisting CFTR trafficking to the apical membrane. Our translational research aims to implement personalized therapy in patients with cystic fibrosis.

Introduction

Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene coding for the CFTR protein. The most frequent mutation is the deletion of the 508th aminoacid (F508del), which affects the folding and trafficking to the membrane of the protein and results in ion transport abnormalities and defective resolution of inflammation in the airways. Recent studies have demonstrated that CFTR mutation-targeted therapies constitute an efficient treatment for CF.

Our research focuses on 3 different aspects:

1. Development of new correctors for F508delCFTR
   Using in silico molecular docking, we have identified compounds which interrupt the interaction between an intermediary filament, keratin 8 (K8), and F508del-CFTR. Inhibition of this interaction restores F508del-CFTR activity. This strategy is extended to other misfolded proteins such as alpha 1 anti-trypsin (AAT-Z mutant) which is involved in A1AT deficiency, another misfolding lossof-function genetic lung disease.
2. Premature Stop codon (PTC) mutations
   The PTCs of the CFTR gene are associated with severe forms as a consequence of truncated, non-functional polypeptides synthesis in concert with the reduction of transcript level by nonsense-mediated decay (NMD). Therapeutic approach aiming at promoting translational readthrough is ineffective so far.
3. Impact of various CFTR mutations and correction on airway epithelial functions.
   This includes in vitro and in vivo regulation of ion transport, airway surface liquid layer height and pH and specialized pro-resolution mediators (lipoxins and resolvins) production.

Research objectives

The first objective is to investigate in deep the mechanisms underlying K8 interaction with misfolded proteins (F508del-CFTR and AAT-Z mutant). The sites of interaction with K8 are actively searched to modulate misfolded proteins trafficking.

The second objective is to optimize the efficacy of the most active correctors by a molecular modeling approach and biophysical technics to get insight into the dynamic structure of the isolated F508del-CFTR 3D structure. We aim to unravel correctors binding sites by directed mutagenesis and to investigate efficacy of these correctors on biogenesis and activity of F508del-CFTR.

The third objective is to develop a more efficacious therapy for nonsense mutations by targeting the molecular pathogenesis of PTCs in CF.

The fourth objective is to establish tools to implement a national program for personalized therapy in CF including a national biobank and characterization of novel biomarkers.

5 main publications

• Odolczyk N, Fritsch J, Norez C, Servel N, da Cunha MF, Bitam S, et al. Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med. 2013;5(10):1484-501.
• Bakouh N, Bienvenu T, Thomas A, Ehrenfeld J, Liote H, Roussel D, et al. Characterization of SLC26A9 in patients with CF-like lung disease.Hum Mutat. 2013;34(10):1404-14.
• Faure G, Bakouh N, Lourdel S, Odolczyk N, Premchandar A, Servel N, et al. Rattlesnake Phospholipase A2 Increases CFTR-Chloride Channel Current and Corrects ∆F508CFTR Dysfunction: Impact in Cystic Fibrosis. J Mol Biol. 2016;428(14):2898-915.
• Le Henaff C, Faria Da Cunha M, Hatton A, Tondelier D, Marty C, Collet C, et al. Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis. Hum Mol Genet. 2016;25(7):1281-93.
• Premchandar A, Kupniewska A, Bonna A, Faure G, Fraczyk T, Roldan A, et al. New insights into interactions between the nucleotide-binding domain of CFTR and keratin 8. Protein Sci. 2017;26(2):343-354.

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