Evaluation of Compound Efficacy for Treating Cystic Fibrosis

Epithelix has a large collection of CF cells with well characterized genotypes established by certified laboratories. MucilAir™-CF replicates the major phenotypes of CF diseases: absence of chloride current, impaired mucociliary clearance, etc. Epithelix possesses the most advanced equipments and expertise for studying the Cystic Fibrosis disease.

Epithelix provides the following services :

1. Evaluation of Corrector, Activator or Potentiator of mutated CFTR on human airway epithelium from Cystic Fibrosis donors (MucilAir™-CF)
2. Evaluation of the mucociliary clearance restoration on human airway epithelium from Cystic Fibrosis donors (MucilAir™-CF)
3. In vitro inhibition of airway mucosa liquid absorption

Cystic fibrosis is a disease caused by mutations of a gene called Cystic Fibrosis Transmembrane Regulator (CFTR). CFTR is a cyclic AMP regulated chloride channel. The most frequent mutation (70% of the patients) is homozygous delta-F508. Instead of being located on the apical surface of the differentiated airway epithelium, the mutated CFTR is trapped in the Endoplasmic Reticulum (ER). As a consequence, the secretion of the chloride is defective, leading to abnormal mucociliary clearance, chronic bacterial infection and inflammation. Therefore, theoretically the most effectively means to treat the CF disease is to restore/improve the function of the mutated CFTR. Depending on the effect of the drugs, the drug candidates could be classified into 3 classes:

1. Corrector, which can help the mutated CFTR to escape from the ER and reach the cytoplasmic membrane.
2. Activator, which can directly activate the normal and/or the mutated CFTR when added to the buffer.
3. Potentiator, which can increase the amplitude/duration of CFTR activation by another activator.

Using different experimental schema, one could assess the effects of the three distinct classes of molecules with Ussing chambers.

See also : Electrophysiology

The above diagram depicts normal airway epithelial ion transport and dysfunctional transport in CF.
Normal airway epithelia (left): CFTR functions as a Cl- transporter and it also regulates Na+ absorption (it inhibits ENaC). The quantity of NaCl on airway surface is optimally regulated to osmotically hydrate the periciliary and mucus layers allowing efficient mucus clearance.
CF airway epithelia (right): In the absence of the CFTR protein in the apical membrane consequent to common CF mutations, such as ΔF508 CFTR, the CF epithelium can exhibit unrestrained Na+ absorption and a failure to secrete Cl-. These combined defects reduce the quantity of NaCl on CF airway surfaces, maintain less water osmotically on CF airway surfaces and, hence, lead to depletion of water in the periciliary liquid layer (PCL) and collapse of a thickened mucus layer onto the epithelial surface.

One of the main problems in the pathology of cystic fibrosis is the poor effectiveness of mucociliary clearance. It inevitably leads to chronic infections of the lungs with pathogens (virus and especially bacteria). Due to recurrent antibiotic treatments, the bacteria become more and more resistant to the antibiotics available on the market.

Improving mucociliary clearance is an effective way to treat CF disease.

Increase of mucociliary clearance upon acute or chronic treatment is easily quantifiable using MucilAir™-CF.

Apical tyloxapol exposure improves mucociliary clearance on MucilAir™-CF in a time-dependant manner.

https://openres.ersjournals.com/content/early/2020/09/17/23120541.00429-2020

https://www.karger.com/Article/FullText/444589