CF Researchers Identify Way to Move Key Mutant Protein to Its Proper Spot in Cells

Collaborative research between Eindhoven University of Technology (Netherlands), McGill University (Canada), and the University of Duisburg-Essen (Germany) has identified a promising approach that could lead to the development of an efficient treatment for cystic fibrosis (CF). The paper, “Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR,” was published in the PNAS journal.

CF is a life-threatening inherited disorder that primarily affects the lungs, but also organs such as the pancreas, liver, intestines, sex organs, and sinuses. It is frequently caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR).

CFTR is involved in the production of mucus, which plays a vital role in processes such as the transport of enzymes in the digestive system and the clearing of bacteria/pathogens from airways. CF patients are particularly susceptible to chronic infections because they have thick and sticky mucus that makes removal and clearing of waste substances from organs difficult.

From a mechanistic standpoint, the CFTR protein in CF patients resides inside mucus-producing cells instead of at the cell wall, as in healthy individuals. Using a new approach, the researchers succeeded in moving the CFTR from inside the cell to the cell wall using a protein called 14-3-3. This protein, present in the cells of healthy individuals, is known to play a very important role in increasing the traffic and transport of CFTR to the cell wall through a specific binding mechanism.

They also demonstrated that a naturally occurring molecule called fusicoccin-A could maintain the interaction between both proteins 14-3-3 and CFTR to ensure better trafficking of CFTR to the cell wall.

These significant results, of which several pharmaceutical companies already displayed interest in acquiring and developing, will require further study to determine if they offer a potentially novel approach for the development of CF therapies. The researchers will seek to investigate if the mutant CFTR located at the cell wall is susceptible of inducing liquid mucus, and to estimate the quantities that will allow for efficiency. Because fusicoccin-A has several drawbacks, such as weak solubility and high cost, researchers also must look into other functional molecules with similar but superior properties in terms of efficiency and cost.

With recently approved cystic fibrosis therapies, such as Kalydeco and Orkambi, treating the underlying cause of the disease and not simply its symptoms, this new research might contribute to next-generation treatment options for patients with CF that further this therapeutic trend.