Novel Therapy Against Cystic Fibrosis Discovered by Researchers

Novel Therapy Against Cystic Fibrosis Discovered by Researchers

A new study led by Dr Gergely Lukacs, from the Physiology Department at McGill University, in Canada, reveals new information about the disease known as cystic fibrosis. Cystic fibrosis (CF), also known as mucoviscidosis, is a life threatening disease that severely affects the digestive system and the lungs. CF is a caused by a genetic disorder that leads to an abnormal transport of sodium and chloride across the epithelium of mucus, sweat, and digestive juices producing cells. This causes the aforementioned secretions to be thick and viscous. According to precedent studies, CF is caused by a mutation in a gene that encodes the protein known as CFTR (cystic fibrosis transmembrane conductance regulator). Even though the discovery of the disease and its cause were made more than 25 years ago, there is no cure for it to this day.

The research team from McGill University reveals novel information about the cause of the CFTR gene mutation, thus offering new potential drug targets. In order to achieve their results, the research team had to first understand the composition of the CFTR protein. The CFTR protein is made up of almost 1,500 amino acids linked together through five domains. Professor Lukacs notes that the quest for discovering an efficient treatment is as hard as trying to repair a tear in a braided rug. Researchers must first identify the origin of the mutation, and then they must discover a way to correct that mutation. “It’s a monumental task”, said Lukacs.

One side of the quest is already complete. Even though there are approximately 2,000 genetic mutations that are associated with the CFTR gene, one of them is more common. Accounting for over 90% of the cases, the genetic mutation known as F508del, involves the deletion of an amino acid found in position 508 of the CFTR protein. According to researchers, this mutation causes the weakening of the protein structure, thus causing it to malfunction.

At the moment, the best drug that could be used to treat cystic fibrosis is called Vertex VX-809. It is currently undergoing clinical trials. However, for the majority of the population that suffers from cystic fibrosis, Vertex VX-809 is a very ineffective drug. Its ineffectiveness is due to the drug only being able to restore the inter-domain communication, whilst being unable to strengthen the domain itself.

Dr Lukacs’ previous studies suggest that the structural effect of the F508del mutation is not restricted to the domain of origin. The mutation also negatively impacts the other four domains of the protein. This translates into a compromise in structural appearance of the protein. To continue the rug analogy, the mutation seems to affect the strength of the rug as a whole, rather than just the strength of a few braids.

In the current study, the research team combined the drug known as Vertex VX-809 with a chemical compound that targeted two structural defects found in the protein. The results of the combination were extraordinary. Through the combination of the two compounds, the efficiency of the drug reached a startling 70%, as compared to the 15% efficiency previously reported in cell cultures.

Dr Lukacs reports that their findings are important because they offer a new way of choosing drug candidates against cystic fibrosis. Moreover, the study shows that the combination of two chemical compounds which target complementary structural defects can increase the effectiveness of drug therapies against cystic fibrosis.