The future of cystic fibrosis treatment

Dr. Daniela Rotin, Theo Moraes, Dr. Felix Ratjen, Dr. Christine Bear, Dr. Janet Rossant, Tanja Gonska (left to right). Photo courtesy of the Hospital for Sick Children.

Paving the way for the next generation of revolutionary cystic fibrosis drugs

February 25, 2016

Cystic fibrosis (CF) is the most common fatal genetic disease affecting children and adults. This devastating disease, characterized by the destruction of the lungs and digestive system complications, is caused by defects in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene and its protein. CF is currently incurable, but new research is providing hope for better treatments—and, ultimately, a cure. 

Dr. Christine Bear from the Hospital for Sick Children and Dr. Russell Viirre from Ryerson University are working in an interdisciplinary environment to improve CF treatments to further-increase the lifespans of patients of this deadly disease.

CF research breakthroughs

The CFTR gene, discovered at The Hospital for Sick Children in Toronto over 25 years ago, produces the CFTR protein that serves as a passageway through the surface of cells lining different organs, including the airways of the lungs. This passageway allows for the movement of salt and water in and out of organs including the lungs to keep the airways hydrated and free of infection. When the gene for CFTR proteins is mutated, major organs become susceptible to severe damage.

Two groundbreaking drugs were recently identified through a process called high-throughput screening, where hundreds of thousands of drug-like molecules are randomly applied to mutated cells until a combination works.

This leaves a critical knowledge gap: We know that these drugs work, but we do not know exactly how or why.

New CF drugs 101

Cystic fibrosis is caused when mutations in the CFTR gene are inherited from both parents. To date, over 2,000 disease-causing mutations have been identified. 

  • G551D affects about 3.1% of CF patients and prevents the passageway formed by the CFTR protein from opening and shutting and keeping organs hydrated.
  • Delta-F508, which accounts for the disease in most patients, prevents the protein from being properly constructed in the first place.

In recent years, two groundbreaking drugs were discovered to fix G551D and Delta-F508: Kalydeco and Orkambi, respectively. These drugs are unique because they directly target the defects caused by mutation.

Understanding CF from the inside-out

Dr. Russell Viirre,
Ryerson University
Photo courtesy of Dr. Russell Viirre.

Dr. Christine Bear,
Hospital for Sick Children
Photo courtesy of the Hospital for Sick Children.

Dr. Bear and Dr. Viirre are very optimistic about the current generation of drugs, but recognize the strong need to understand them on a deeper level. "There will almost certainly be a need for a new generation of these drugs," Dr. Viirre explains. "If we can understand, at a molecular level, exactly where and how Kalydeco and Orkambi interact with the CFTR protein, it will be possible to develop a new generation of these drugs that interacts even more effectively with that protein – and not by random chance."

His team is doing just that with molecular tracking systems called chemical probes. This unique approach to tracking drug activity, paired with the support of pharmaceutical companies and Dr. Bear’s expertise on CFTR, could pave the way for a new generation of drugs that is more potent, more effective and with a smaller risk of side-effects than the current drugs. "This is the kind of research that is going to impact long-term treatment," says Dr. Viirre.

This CIHR-funded study is setting the bar for future research in the field. Norma Beauchamp, President and CEO of Cystic Fibrosis Canada, agrees. "The pace of development in the area of cystic fibrosis research and drug development is exciting. This interdisciplinary partnership will get us closer to our vision of a world without CF," she says.

"I think this is a story of collaboration that CIHR and Cystic Fibrosis Canada should be proud of. Not only is this research interdisciplinary on the academic front, but it reaches out to clinical researchers and pharmaceutical companies who have allowed us to develop better probes and better drugs.

Dr. Christine Bear, CIHR-funded researcher, Hospital for Sick Children

In Canada, CF patients live until they are about 50 years old, which is 20 years longer than they did in 1990, and Dr. Bear believes that these mutation-targeted therapies might be the breakthrough needed to extend their lives even further. "This is a very exciting time," says Dr. Bear. "These recent drug discoveries are motivations for researchers and pharmaceutical companies to do even better because we now have evidence that it is possible."

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