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About Sickkids
About SickKids

September 16, 2014

25 years later: the impact of the cystic fibrosis gene discovery

Dr. Lap-Chee Tsui visits CF drug discovery lab at SickKids to commemorate gene discovery

TORONTO – Melissa Benoit spent the first month of her life in the neonatal intensive care unit at The Hospital for Sick Children (SickKids) where she was diagnosed with a fatal genetic disease called cystic fibrosis (CF). It was 1983 and at that time, the life expectancy for someone with CF was just 12 years old, in the US and around 20 in Canada.

In 1989, just a few years later, a team of researchers led by Dr. Lap-Chee Tsui at The Hospital for Sick Children (SickKids) made a breakthrough that would not only impact the lives of children with CF but would also pave the way for what is now known as individualized medicine. The team discovered the gene that causes cystic fibrosis, a disease that primarily affects the lungs and digestive system. CFTR was the first disease-causing gene to be identified and at the time was touted as “one of the most significant discoveries in the history of human genetics.”

This September, SickKids celebrates the 25th anniversary of the CF gene discovery and the progress that has been made both clinically and scientifically. Thanks to medical and research advances, today Benoit is a 31-year-old nurse, wife and new mom; something that may not have been possible without this genetic breakthrough 25 years ago.

“Finding the gene opened the door to unprecedented knowledge of the disease. After its discovery we were able to study and understand how the protein made by the CFTR gene worked and what happened when it didn’t,” says Dr. Christine Bear, Senior Scientist and Co-Director of the CF Centre at SickKids. “Once we figured this out, therapy that targeted defects caused by CF gene mutations could begin.”

Today, the goal of CF researchers is to create effective therapies for every CF patient. “The vision is that the genetic signature of each CF patient will dictate the choice of therapy.  This approach will ensure the best clinical response with least number of side effects for each individual,” says Dr. Felix Ratjen, Head of Respiratory Medicine, Senior Scientist and Co-Director of the CF Centre at SickKids. “Our team is currently working on patient-specific drug development for the first time in cystic fibrosis research.”

After the CF gene discovery in 1989, Tsui set up a mutation database that would house the collection of mutations in the CF gene so researchers around the world could benefit from the most up-to-date genetic information about the disease. This database remains a major resource for clinical and basic research and serves as a model for other genetic disease databases. In total there are over 1,900 mutations in the CF gene. Scientists have learned that many of these can be classified with respect to the type of defect they cause in the protein. Gaining this understanding has driven the race to find mutation-targeted therapeutics. 

“We are at a new frontier of discovery for CF patients,” adds Bear. “Over the past decade there has been tremendous progress with regards to therapy discovery conducted using generic cells induced to possess a particular CF mutant protein. These “work horse” cell cultures were then used to identify the types of chemical compounds that can repair the defect caused by that specific mutation. However, there were limitations since these cells did not exactly mimic the cell in the lungs, liver or pancreas of CF patients. While this approach led to the discovery of one drug called KALYDECOTM, we believe that a new discovery strategy is needed during the upcoming 10 years to find the next generation of therapies effective in treating all CF patients.” 

The CF story at SickKids has always been one of collaboration. The gene discovery was a partnership between SickKids and the University of Michigan; the creation of the CF mutation database is an international collaboration; and the most recently, the pharmaceutical and philanthropic communities and SickKids came together to develop the first mutation-targeted CF drug, KALYDECO. 

The recent approval of KALYDECO as a drug for some CF patients with specific mutations is evidence that compounds found to repair the primary defect caused by a mutation in the lab, can be translated into drugs that improve the health of CF patients. “While this is a big step for CF, there is still much work to be done, because this treatment is only effective for a small population of CF patients. We know that a variety of therapies will be needed to make a difference for more CF patients, not only because there are many different CFTR mutations but also because of the uniqueness of each patient. As we speak, we are developing new ways for discover therapies that employ airway cells like those that are affected in CF patients,” says Bear.

The CF Centre at SickKids is focusing its efforts on identifying new lung cell-targeted therapies by testing for compounds that rescue mutant CFTR function. These tests are conducted by robots applying drugs on thousands of tiny wells, with each well each containing cells with a particular CFTR mutation. Scientists can see in real time whether a drug is rescuing mutant CFTR function or not. The top compounds identified in these robotic screens will be tested on cells from individual patients with the goal of finding the best therapy for each individual.

“The key to our continued success has been the partnership with patients and families. Clinicians, scientists and patients are working together to advance treatment and improve outcomes for children and adults living with the disease,” adds Ratjen.

Benoit has been participating in CF research since she was around nine years old, and some of the experimental therapies she tried as a child are now the standard treatment for children born with the disease.

“We wouldn’t be where we are today without ongoing research. In my lifetime alone, the research advances that have been made have had a huge impact on my quality of life and certainly on others living with cystic fibrosis as well,” she says. “If my participation in research can help scientists gain a better understanding of the disease and ultimately improve outcomes for those living with cystic fibrosis, then why not?”


CF discovery photo gallery      Melissa Benoit photo gallery

Cystic fibrosis                                                          Melissa Benoit


Cystic fibrosis at the PGCRL