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Cystic fibrosis (CF) is a chronic disease that impacts the lungs and digestive system. It affects about 70,000 people worldwide and it’s the most common fatal genetic disease among children and young adults in Canada. There is no cure for CF and, until now, it was only possible to treat the symptoms of the disease. However, a newly-released drug called Kalydeco promises to target the root cause of CF at the molecular level.

Understanding CF

Fast fact: You have about 20,000 different genes, which are specific segments of the DNA in your cells. Genes provide the instructions for making molecules called proteins.CF is caused by a defective Cystic Fibrosis Transmembrane Regulator CFTR protein, which is located on the surface of your cells. This protein is important for the regulation of mucus, sweat, and digestive juices. When it doesn't work properly because of a mutation in the CFTR gene, the movement of water in and out of cells is disrupted, causing abnormally thick mucus to build up in the lungs and digestive tract.

This thick mucus clogs the lungs, making it difficult to breathe causing life-threatening lung damage and disease. In addition, thick mucus build-up in the digestive tract makes it difficult to digest food and absorb nutrients. Symptoms of CF include salty skin, persistent coughing, shortness of breath, and impaired growth.

In recent decades, a better understanding of the disease has led to treatments that can tremendously improve the quality of life of people with CF. In the 1950s, children diagnosed with CF rarely lived more than four years. Today, people with CF regularly live into middle age and beyond.

Treatments include airway clearance to remove mucus from the lungs and pancreatic enzyme supplements to help nutrient absorption. However, these treatments only target the symptoms of the disease.

A new drug called Kalydeco directly targets the root cause of CF and not just the symptoms. It is the first drug of this kind!

How Kalydeco works

Fast fact: A mutation is a permanent change in the DNA sequence of a gene. These changes affect the proteins produced by the gene. For example, a protein might be located in a different part of the cell or it might not work properly.Approved by the U.S. Food and Drug Administration in January 2012—and subsequently approved in Canada, Australia and the European Union—Kalydeco is the only available drug that directly improves the function of the faulty CFTR protein. It can be taken by CF patients with a specific CFTR mutation called G551D, which is found in 3.4% of those affected by CF in Canada.

The G551D mutation causes the production of a CFTR protein that is properly located on the surface of the cell. However, the defective protein acts like a locked gate, refusing to open to allow salts and fluids to flow properly in and out of the cell. Kalydeco actually unlocks the closed CFTR gate, restoring the normal flow of salt and fluids in the lungs and thinning the thick mucus that builds up in people with CF.

Unfortunately, G551D is only one of 1900 different mutations in the CFTR gene that have been identified. Delta F508 is the most common mutation, found in 91.5% of patients on the Canadian Cystic Fibrosis Registry in 2011. This mutation causes the production of a CFTR protein that doesn’t properly move to the cell surface at all.

So, for the moment, Kalydeco can only help a small fraction of people with CF. But hopefully it can also serve as a model for developing new drugs that will address the root causes of CF in people with mutations other than G551D. In the same way as Kalydeco, these drugs could correct the problems with the faulty CFTR gene and prevent the faulty protein that causes CF symptoms from ever being produced.

References

About Cystic Fibrosis (Cystic Fibrosis Foundation) The Canadian CF Registry (Cystic Fibrosis Canada) The Facts about Cystic Fibrosis (Cystic Fibrosis Canada) Kalydeco (Cystic Fibrosis Foundation) What is a gene? (US National Library of Medicine/Genetics Home Reference) What is a gene mutation and how do mutations occur? (US National Library of Medicine/Genetics Home Reference) What is cystic fibrosis? What causes cystic fibrosis? (Peter Crosta, Medical News Today)

Anna Zhou

I completed my BSc at McMaster University in Biochemistry and am now pursuing my MSc in Medical Biophysics at the University of Toronto. I am located at the SickKids research building in downtown Toronto and am researching the structure of the ATP synthase using electron microscopy. In my spare time, I love to dance, read and explore the city.

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