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Landmark Advancement in Cystic Fibrosis Therapy

The Cystic Fibrosis (CF) community celebrates a landmark achievement this fall. For the first time, a highly effective medication is available to treat the underlying cause of CF for 90% of people with this life-threatening genetic disease. CF causes frequent lung infections, progressive lung disease, and malnutrition due to abnormally thick mucus in the lungs and pancreas.

Trikafta™ received fast-track FDA approval thanks to significant improvement in lung function, reduced flare-ups, improved symptoms, and weight gain in people with CF who have at least one copy of the most common CF mutation (CFTRF508del).

CF occurs as a result of mutations in the CFTR gene. A person with one CFTR mutation is a carrier and generally unaffected. A person with two CFTR mutations usually has Cystic Fibrosis. The CFTR gene instructs cells to make the CFTR protein, a chloride channel that is necessary for fluid regulation.

When CFTR protein is absent or not working, mucus builds up and leads to multi-system disease. The first modern description of CF occurred in 1938 when children with the condition typically did not live to attend kindergarten. Treatments including digestive enzymes, antibiotics, and techniques for mucus clearance help the symptoms of CF and have steadily improved length and quality of life. The CFTR gene was discovered in 1989. At that time, life expectancy was 25 years. The discovery of the gene enabled better testing, including molecular diagnosis and carrier testing, and raised new hope for game-changing therapies like Trikafta and perhaps one day, gene therapy.

Over 1500 mutations in the CFTR gene have varying impacts on the CFTR protein. The most common mutation is F508del, which causes the abnormal CFTR protein to be broken down instead of reaching the cell membrane. Ninety percent of people with CF have at least one copy of CFTR F508del. The first medication to target the genetic cause of CF instead of its symptoms was Kalydeco® in 2012. Kalydeco was approved for people with the CFTR G551D mutation (~5% of people with CF). Orkambi® was approved in 2014 for individuals with two copies of CFTR F508del, but this offered only modest improvements. Trikafta, approved in October 2019, could offer dramatic improvements for 90% of people with CF.

The median life expectancy in CF is now 48 years and improving. Many people with CF achieve milestones including college, career, marriage, and children, and the future is only looking brighter. The CF story proves that genetic discovery, combined with engaged researchers and patients, can shape medical breakthroughs. Other strategies, such as mRNA therapies, gene therapy, and gene editing may one day help the 10% of people with CF that don’t respond to medications like Trikafta. The scientific race has begun to deliver such treatments for all people with CF, as well as those with other genetic diseases.

Francis Collins, physician-geneticist and director of the NIH, was involved in the discovery of the CF gene and led the Human Genome Project. After discovering the CF gene, he wrote a song called Dare to Dream. He updated the lyrics to reflect recent progress and performed it at the 2019 North American Cystic Fibrosis Conference.