• Wednesday, 08 July 2020 - 00:53:52

Cystic fibrosis : physiopathology and phenogenomics

Harriet Corvol
Team Leader : Harriet Corvol
Administrative contact : Erwan Leforestier

Hopital Saint-Antoine - Bâtiment Kourilsky - 6ème étage - 184, rue du Faubourg Saint-Antoine, 75012 Paris, France

Professors, Lecturers, Researchers, Clinicians
Postdocs, Contract Researchers, Emeritus, Volunteer
Engineers, Technicians
PhD students, Master

Research cystic fibrosis physiopathology and phenogenomics

Cystic fibrosis (CF) is the most common, severe, autosomal recessive genetic disease in Caucasians due to pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene. More than 2000 CFTR variants have been described, the most common being the F508del. Although CF is considered to be a monogenic disease, significant phenotypic diversity is observed in patients with the same CFTR variants. In addition to environmental factors, it has been shown that other genes, called modifier genes, contribute to this variability. This disease affects several organs such as the pancreas, liver, intestine, and more severely the lungs. At the airway level, the absence of a functional CFTR leads to defective water and salt transport, resulting in impaired mucociliary clearance, chronic infections, exacerbated inflammation, and destruction of the lung tissue. Lung damage remains the main cause of morbidity and mortality in CF.

Four main areas of research in CF are studied in our laboratory: identification and evaluation of modifier genes, role of chloride channels, inflammatory/anti-inflammatory response and infectious response.

Modifier genes study in CF

Our team coordinates a national study on CF modifier genes and participates in international networks. More than 4800 French patients are participating in this study.
Following analyses of the whole genome (GWAS), we identified and validated the role of multiple genes in several CF clinical disorders such as lung disease (Corvol et al, Nat Commun 2015), meconium ileus (Sun et al, Nat Genet 2012), Immunotrypsinogen and sweat chloride measurements (Miller et al, J Pediatr 2015, Collaco et al. Am J Respir Crit Care Med 2016), and drug response (Strug et al, Hum Mol Genet 2017 & Corvol et al, Front Pharmacol 2018). We pursue our analyses to discover genes associated with other CF traits such as diabetes and liver disease (Boelle et al, Hepatology 2018), and to functionally characterize the identified genes.

Role of FAM13A as a CF modifier gene

We have recently identified FAM13A as a CF lung disease modifier (Corvol et al, J Med Genet. 2014). The functional study of FAM13A has shown that its inhibition leads to a disorganization of the actin-F cytoskeleton and formation of stress fibers, and regulates markers of the epithelial-mesenchymal transition (Corvol et al, J Cyst Fibros 2018). We are currently working on mice models in collaboration with North American teams.

Therapeutic strategy targeting RNAs

New therapeutic strategies targeting CFTR RNAs are being evaluated in several laboratories (Sonneville et al, Am J Pathol. 2015; Bardin et al, Front Pharmacol, 2018; Bardin et al, Med Sci, 2018). In order to propose an alternative therapeutic approach targeting all patients, regardless of the CFTR variants, we have developed a molecule blocking a microRNA which itself negatively regulates the ANO1 chloride channel (3 international patents). In in vitro and mice models, we have shown that this molecule was able to compensate for some CFTR defects (Sonneville et al, Nat Commun. 2017). Our current objective is to develop this molecule in order to consider an alternative therapeutic strategy for all CF patients. At the same time, we have also shown that some miRNAs were involved in the pulmonary inflammation observed in CF patients (Bardin et al, J Pathol, 2018), work that is currently ongoing.

Study of the response of bronchial epithelial cells following an infection by

  • Pseudomonas aeruginosa: Analyses of mRNAs and long non-coding RNAs expressed by bronchial epithelial cells during P. aeruginosa infection show significant differences in expression between cells of CF patients and healthy subjects (Balloy et al, PLoS One. 2015 & Front Cell Infect Microbiol. 2017). Following these transcriptomic analyses, we have recently highlighted the role of CHAC1 in the control of inflammation (Perra et al, Front immunol, 2018). We are currently analyzing miRNA expression during P. aeruginosa infection.
  • Aspergillus fumigatus: Bronchial epithelial cells inhibit the growth of the fungus A. fumigatus by a PI3 kinase-dependent process (Richard et al. Sci rep, 2018). Transcriptomic analysis of infected cells will allow us to identify the genes involved in this anti-fungal activity in order to describe their role in the fungal infection in patients with CF.

2018 highlights

CF modifier genes

In collaboration with North-American teams, we identified and validated the role of multiple genes in several CF clinical disorders such as lung disease (Corvol et al, Nat Commun 2015), meconium ileus (Sun et al, Nat Genet 2012), Immunotrypsinogen and sweat chloride measurements (Miller et al, J Pediatr 2015, Collaco et al. Am J Respir Crit Care Med 2016), and drug response (Strug et al, Hum Mol Genet 2017 & Corvol et al, Front Pharmacol 2018). We helped to develop new biostatistical models to evaluate modifier genes (Soave et al. Am J Hum Genet 2015). In 2018, we analyzed the cumulative incidence, the complications and risk factors for CF liver disease (Boelle et al, Hepatology, 2018).

We have functionally analyzed one CF lung disease modifier, FAM13A1 (Corvol et al. J Med Genet 2014) and studied its role in vitro. We have shown that its inhibition led to a disorganization of the actin-F cytoskeleton and formation of stress fibers, and regulated markers of the epithelial-mesenchymal transition (Corvol et al, J Cyst Fibros 2018). We are currently working on mice models in collaboration with North American teams.

Therapeutic strategy targeting the chloride channel ANO1 ads the inflammation

This project, supported by the SATT Lutech as part of a valorisation program in partnership with Inserm Transfert, is one of the strategic projects of the French CF patients foundation “Vaincre La Mucoviscidose”. An international patent was published by Inserm Transfert in 2016 (PCT/EP2016/065565) and two others were filed in 2018 for this molecule which could have therapeutic application for all patients with CF. The new molecule blocks a miRNA which itself negatively regulates the ANO1 chloride channel. In in vitro and mice models, we have shown that this molecule was able to compensate for some CFTR defects (Sonneville et al, Nat Commun. 2017). Our current objective is to develop this molecule in order to consider an alternative therapeutic strategy for all CF patients. At the same time, we have also shown that some miRNAs were involved in the pulmonary inflammation observed in CF patients (Bardin et al, J Pathol, 2018.

Study of the response of bronchial epithelial cells following an infection by

  • Pseudomonas aeruginosa: Analyses of mRNAs and long non-coding RNAs expressed by bronchial epithelial cells during P. aeruginosa infection show significant differences in expression between cells of CF patients and healthy subjects (Balloy et al, PLoS One. 2015 & Front Cell Infect Microbiol. 2017). Following these transcriptomic analyses, we have recently highlighted the role of CHAC1 in the control of inflammation (Perra et al, Front immunol, 2018). We are currently analyzing miRNA expression during P. aeruginosa infection.
  • Aspergillus fumigatus: Bronchial epithelial cells inhibit the growth of the fungus A. fumigatus by a PI3 kinase-dependent process (Richard et al. Sci rep, 2018). Transcriptomic analysis of infected cells will allow us to identify the genes involved in this anti-fungal activity in order to describe their role in the fungal infection in patients with CF.

Saint-Antoine
Research Center
UMR_S 938

Hôpital St-Antoine

Contact

Phone : +(33) 1 49 28 46 00