Cystic Fibrosis: CFTR Trafficking
Cystic fibrosis is caused by mutations in the protein CFTR, an ion channel that is expressed in several organs, but most notably the lung and pancreas.
In the lung, CFTR is responsible for maintaining a thin water layer above the cells of the lung epithelium (that layer of cells the separates your lung from the air that you breath in). When CFTR is mutated it is not able to maintain that water layer, and mucous builds up. In the absence of the water layer, this mucous cannot be cleared, your lungs can’t get enough oxygen to your blood, and bacteria begin to take up residence. There are problems associated with the pancreas as well, but the main pathology is poor lung function and chronic lung infection
There are a variety of different mutations that can lead to CFTR malfunction, but the most common involves the deletion of a single amino acid in a protein strand containing 1480 amino acids. Roughly 70% of CF patients have this single mutation, called deltaF508 (shorthand for deletion of Phenylalanine 508).
deltaF508 causes a folding defect. The protein is made in the usual amounts, but it doesn’t fold properly, and can’t make its way through the machinery that takes proteins from where they’re made to their place on the protein surface. The misfolded protein is eventually degraded. The small amount of mutated protein that does get to the surface does seem to pump chloride normally, but it just can’t do enough to maintain the water layer.
Sharp Edge Labs uses our trafficking technology to directly monitor the movement of deltaF508 to the cell surface. With this technology we can tell if a compound acts as a “chemical chaperone” enabling CFTR to get through the trafficking machinery and to the cell surface. The company is screening compounds libraries in search of compounds that will restore enough CFTR to the surface to improve lung function for patients with CF.
To validate the compounds discovered in our screens we’ll use stem cells from CF patients to show functional rescue of the CFTR channel.