The research decision to focus on fixing CFTR proteins, rather than the CFTR gene, brought a "big uplift in therapeutic success," says UAB researcher Steven Rowe. The research decision to focus on fixing CFTR proteins, rather than the CFTR gene, brought a "big uplift in therapeutic success," says UAB researcher Steven Rowe.

How did we get here? Cystic fibrosis drugs go from 0-90 percent effective in a few short years

November 05, 2018
By Matt Windsor
The "high-risk" decision to focus on fixing CFTR proteins, rather than the CFTR gene itself, has brought major improvements in lung function and quality of life.

This is the second part of a series exploring breakthroughs in cystic fibrosis research that are paving the way for new treatments to help millions with other diseases, including COPD, asthma and more. Read part one, After cystic fibrosis 'miracle,' researchers are exploring ways to reach millions more.


Despite early hopes for gene therapy cures for cystic fibrosis, “the field underestimated how difficult it would be to make them work,” explains Steven Rowe, M.D., director of the UAB Gregory Fleming James Cystic Fibrosis Research Center. (Gene therapy approaches are still being studied and have potential, he notes.) “It was only when we said, ‘Let’s try to fix the protein rather than the gene,’ that we had this big uplift in therapeutic success.”

Toward protein-based treatment

Fixing a protein, unlike fixing a gene, can mean correcting a whole series of errors. The CFTR protein is a gatekeeper. Its station is in the cell membrane, where it allows a variety of substances, including chloride, bicarbonate and ultimately water, to pass in and out of the cell, and acts as a “master regulator of hydration status,” says George Solomon, M.D., a researcher in the UAB CF Center and assistant professor in the Division of Pulmonary, Allergy and Critical Medicine in the UAB School of Medicine. There are plenty of ways it can go wrong. Just short of 2,000 mutations have been documented in the CFTR gene, which is the template for making the CFTR protein; hundreds of those mutations are known to lead to CF symptoms.

mix cf know your mutationsThis graphic from the Cystic Fibrosis Foundation illustrates normal CFTR functioning (far left) and the different types of mutation classes in cystic fibrosis. Image courtesy Cystic Fibrosis Foundation.

'Very high-risk'

The end result is generally the same: dehydrated airways and deranged mucus. But the specific cause in any individual case goes back to the mutation. Some patients have mutations that affect the CFTR channel itself, preventing it from opening properly. Other mutations cause the CFTR proteins to become misfolded, so that they never even reach the cell membrane. With all this molecular chaos, could a protein-based treatment ever work? Many in the field were doubtful. The focus on protein repair “was considered very high-risk at the time,” Rowe says. “But it has paid dividends.”

Groundbreaking trials

And how. When pharmaceutical company Vertex found promising drug candidates, tests developed in Rowe’s lab helped home in on the compounds most likely to improve CFTR protein function. UAB patients were some of the earliest enrollees in the groundbreaking trials of Vertex’s drug ivacaftor, the first protein-focused treatment for cystic fibrosis, which received FDA approval in 2012. “The first time we treated patients with ivacaftor,” in a clinical trial a few years earlier, “We got a call from one patient within a couple of days,” Rowe says. “She said, ‘I’m finally coughing up all this mucus.’ We knew something good might be happening.”

After a lifetime of needing family members to pound out their recalcitrant mucus, patients were getting rid of it on their own. They could breathe more easily. Follow-up studies found that patients could fight off seemingly fatal infections when they were on ivacaftor. Children were growing bigger and stronger. “Ivacaftor is like a modern-day miracle drug for some patients,” says Jennifer Guimbellot, M.D., Ph.D., a pediatric pulmonologist, assistant professor in the Department of Pediatrics and researcher in the UAB CF Center. “I’ve seen remarkable improvements in my patients.”


UAB researcher George Solomon explains advances in CF therapies in this video from the Cystic Fibrosis Foundation. Video courtesy Cystic Fibrosis Foundation.


Beyond gating mutations

But ivacaftor was always only the tip of the iceberg. A mere 4-6 percent of CF patients have the “gating” mutations that ivacaftor targets, in which CFTR channels cannot open. For the vast majority of patients, the problem is misfolded proteins. Still, the success of ivacaftor “brought a lot of others into the field,” Rowe says.

Correctors, a new class of drugs that help proteins fold properly, arrived a few years ago. They were only partially effective on their own, says Rowe. But in major multi-center trials that he co-led, combinations of correctors and ivacaftor have brought significant improvement. Currently, some 15 percent of patients have highly effective CFTR-directed therapies available, and another 50 percent also benefit from these potentiator-corrector combinations.

The triple combo

The next step is the triple combination. Rowe is now co-leading large studies of drugs that combine two correctors plus ivacaftor, to bring even more channels to the membrane. Results from phase 2 trials, reported in October in the New England Journal of Medicine, have been just as impressive as the original ivacaftor studies, he says, including “major improvements in lung function and quality of life.” Even the sweat test, the harbinger of bad things known to the taste buds of mothers and infants, began to normalize. If these responses continue in phase 3 trials, up to 90 percent of CF patients will have highly effective CFTR therapy.

Even seemingly minor improvements can make a major difference, Rowe notes. In a recent commentary in Lancet Respiratory Medicine, he explains that reducing the average rate of decline in a 20-year-old patient by a single percentage point, from 4 percent to 3 percent per year, would add an extra 6-8 years of life. “We’re on the brink of seeing this through from vision to execution and availability,” he says.


Continue on to part three, Attacking nonsense mutations in cystic fibrosis and a host of other diseases.