There was once little hope for a child diagnosed with cystic fibrosis (CF)—a genetic disease that can lead to frequent lung infections, pancreatic insufficiency, and infertility—to finish elementary school, attend college, pursue a career, or have children. CF occurs when the cystic fibrosis transmembrane conductance regulatory (CFTR) protein is dysfunctional, not produced, or not produced in sufficient quantities to transport chloride ions to the surface of lung cells. Without chloride transport, there is less water transport to these cell surfaces, causing mucus buildup that traps bacteria and fungus that leads to infections. More than 1,700 CFTR gene mutations have been detected, the most common being F508del.
But the past 30 years of research has completely changed the prognosis. In yesterday’s plenary session, “The Remarkable Journey from Bench to Bedside: Changing Lives of Individuals with Cystic Fibrosis,” Bonnie Ramsey, MD, director of the Center for Clinical and Translational Research at Seattle Children’s Research Institute and professor and vice chair for research in the department of pediatrics at Seattle Children’s Hospital, recounted her scientific journey in developing CFTR modulators.
One of the highlights of her career was in the late 1970s, when she and her colleagues developed an inhaled formulation of tobramycin. Prior to this formulation, patients received intravenous tobramycin, which was insufficient to obtain the lethal doses of the drug in the lungs necessary to adequately fight off infection. With the inhaled formulation, they could effectively administer doses 10-20 times higher at the site of infection.
When Ramsey first saw the data, she was “absolutely astounded to see over 99 percent killing of pseudomas.” This drug gained FDA approval for the treatment of CF in 1975, which not only revolutionized care for CF patients, allowing them significantly more time away from the hospital, but also set up the FDA approval pathway for other inhaled antibiotics.
From there, Ramsey went on to help set up the Cystic Fibrosis Therapeutics Development Network, a group that now includes more than 72 hospitals to conduct clinical trials on CF modulators. Their most recent success story was the 2019 FDA approval of a triple combination therapy of elexacaftor/ivacaftor/tezacaftor for patients 12 years of age or older with at least one F508del mutation, a population which accounts for about 93 percent of patients with CF.
What can the field of laboratory medicine do to help support patients with CF? Ramsey pointed to the lab’s critical role in monitoring patients receiving CF modulators for changes in liver enzymes. She also highlighted the potential role in helping elucidate the natural history of this disease through observational studies of laboratory tests.
Like all good stories, this one includes a twist. Ramsey didn’t originally set out to become a CF pulmonologist determined to discover treatments for CF. She “fell into” the role, she said, originally intending to be a pediatric hematology oncologist. But she “fell in love with the patients, fell in love with the clinic.” What does Ramsey have to say to young scientists? “Dream. I never thought it would be possible to cure this disease, and we’re getting pretty close to that.”
Attendees also heard from Caley Mauch, a cystic fibrosis survivor and public speaker for the Cystic Fibrosis Foundation, about how these modulators have changed her life. Mauch described how prior to starting the triple combination therapy, even simple colds could result in weeks-long hospital stays. But thanks to the tremendous effort of scientists and physicians like Ramsey, Mauch says she has “never felt better; never felt more normal.”
The story does not end here. Ramsey and colleagues are now exploring genetic therapies that go beyond symptom management and may, in fact, hold the key to a cure for cystic fibrosis.