With two FDA-approved drugs on the market and several more in the pipeline,
expectations of long-term survival run high as an era of personalized medicine

by Tim Bonfield 

As recently as 1980, most children born with cystic fibrosis (CF) could not expect to live long enough to legally buy a glass of wine.

Now, growing numbers of CF survivors can look forward to toasting their own retirements thanks to a wave of scientific breakthroughs that has begun to conquer a feared childhood killer.

John Clancy, MD.

John Clancy, MD, Research Director for the Division of Pulmonary Medicine at Cincinnati Children’s.

“We are rapidly moving toward the day when people will live long, full lives and ultimately die with cystic fibrosis instead of dying prematurely of cystic fibrosis,” says John Clancy, MD, research director for the Division of Pulmonary Medicine at Cincinnati Children’s.

The advanced research and state-of-the-art treatment provided through the Cystic Fibrosis Center at Cincinnati Children’s are two of several reasons why U.S. News & World Report recently ranked the medical center as the nation’s best for pediatric pulmonology. Cincinnati Children’s is one of only 10 Cystic Fibrosis Foundation Research Centers in the United States and one of the first centers to join the foundation’s Therapeutics Development Network. Researchers here have supported CF drug discovery and development from the early days.

Clancy has served in various research leadership roles with the CF Foundation and currently serves as chair of the NIH Rare Disease Research Network. He was a co-author of the seminal paper, published in 2010 in the New England Journal of Medicine, which unveiled the world’s first medication proven to act upon the root causes of cystic fibrosis. Clancy’s role included reviewing the blinded data for one of the key biomarkers in the study.

That once experimental drug, VX-770, became ivacaftor (now marketed as Kalydeco), which won U.S. Food and Drug Administration approval in 2012. This drug has a powerful effect on cystic fibrosis patients with a mutated version of the gene G551D-CFTR, and similar mutations. For these 5 percent to 7 percent of patients, the drug can restore lung function from near zero capacity to better than 50 percent of normal, Clancy says.

Clancy also was lead author of the first published study of lumacaftor in CF patients, which became part of the newest CF drug, which won FDA approval in July 2015. Dubbed Orkambi, this combination treatment (lumacaftor 200 mg/ivacaftor 125 mg) is not quite as dramatic as Kalydeco as it increases lung function to about 15 percent of normal. However, the treatment works against the most common genetic cause of CF, those who have two copies of the F508del mutation. About 45 percent of the 30,000 people with CF in the United States have two copies of this gene mutation.

“Fifteen percent lung function is still a long way from normal, but that level of function can make it possible for many more people to survive much longer,” Clancy says. “More importantly for survival, the clinical trial showed a 40 percent decrease in pulmonary exacerbations. For many CF patients, these episodes of inflammation and infection have become leading predictors of lung function decline and death.”

As important as the two new drugs may be, even more treatments are coming.


Anjaparavanda Naren, PhD, Co-Director of the Cystic Fibrosis Research Center and his research team, Chang Suk Moon, PhD, and Kavisha Arora, PhD.

Anjaparavanda Naren, PhD, Co-Director of the Cystic Fibrosis Research Center and his research team, Chang Suk Moon, PhD, and Kavisha Arora, PhD.

Now the race is on to develop more medications to address all of the emerging classes of CF patients. Some of those advances will likely be based upon the work of a research team led by Anjaparavanda Naren, PhD, co-director of the Cystic Fibrosis Research Center.

CF has become a prime example of the potential power of personalized medicine, Naren says. Since the discovery of the cystic fibrosis transmembrane conduct regulator gene (CFTR) in 1989, researchers have gone on to find more than 1,900 mutations of the gene. The sheer variety of mutations means that no single drug is likely to have a cure-all effect. Instead, clinicians will need to build genetic profiles of each patient, and then tailor treatments accordingly.

Clancy and Raouf Amin, MD, Director of the Division of Pulmonary Medicine, recruited Naren to Cincinnati Children’s in 2013. Now Naren works to expand the connections between CF-related mutations and drugs known to act upon them.

Earlier this year, Naren and his research team, including Chang Suk Moon, PhD, and Kavisha Arora, PhD, reported finding an interplay between CFTR and the multidrug resistance protein 4 (MRP4). In cystic fibrosis, chloride channels on epithelial cells underperform, keeping fluids in the lungs. In diarrhea, the channel over-performs, releasing fluids into the intestines and bowel.

The study was featured on the May 1, 2015, cover of The Journal of Biological Chemistry for two reasons. The chloride channel findings have potentially broad implications for controlling medication-induced diarrhea, an all-too-common therapy side effect for diseases far beyond cystic fibrosis. In addition, the model the scientists developed to conduct the study has its own implications.


Naren’s team, in collaboration with Michael Helmrath, MD, successfully developed intestinal organoids he calls “enteroids,” which were grown from stem cells obtained from tiny amounts of biopsy material. The enteroids functioned as living test platforms that allowed the team to evaluate the effects of drug exposures in real time.

“Until now, we did not have a good model system to study intestinal biopsies, because the tissue samples that could be safely collected have been so small,” Naren says. “Now we have multiple approaches.”

Enteroids like these will help accelerate cystic fibrosis drug development and the larger concept of genome-based personal treatment.

“Enteroids allow us to use stem-cell techniques to develop a better index of chloride channel function, which gives us the kinds of tools we need to move into personalized medicine,” Naren says.

Cincinnati Children’s has played a leading role in organoid research. James Wells, PhD, was among the first to succeed at developing functional intestine and stomach tissues from induced pluripotent stem cells (iPSCs). Wells and Helmrath have collaborated to demonstrate a method to grow human organoids to much larger sizes in mice, which suggests that organoids created from a patient’s own cells may be able to grow on their own once implanted. Naren has been working with both of these scientists to advance treatment for cystic fibrosis.

“One of the reasons I came to Cincinnati was the unique opportunity for collaboration here,” Naren says.

At Cincinnati Children’s, Naren has gained greatly expanded access to human tissue samples and new opportunities to connect his once-isolated animal-based research directly to the human clinical trial pipeline. He has collaborated with experts in fields ranging from endocrinology to bioinformatics. He also found the funding to build the customized equipment needed to obtain confocal microscope imagery of living enteroids in action.


Here, personalized medicine is no longer an abstract goal; it is an expanding reality, Naren says. For example, he recently worked with Clancy and Gary Lewis McPhail, MD, the director of the Division of Pulmonary Medicine’s Cystic Fibrosis Center, to successfully treat three CF children from the United Arab Emirates.

The team determined through DNA sequence information that the children shared a specific S549N mutation of the CFTR gene. Naren was familiar with this mutation through previous research he published in 2012. The team agreed that this unusual CFTR mutation was similar enough to the G551D mutation affected by Kalydeco to believe the drug would help.

Prescribed off-label, the daily drug regimen has worked. Within a month, sweat chloride levels for the children had dropped to near normal, FEV1 tests of lung capacity had improved, and their CF-driven insulin resistance had resolved, Naren says.

This is the personalized medicine revolution coming for children with cystic fibrosis, and eventually for children with all sorts of rare diseases, Naren says. Treatment flow will move from the patient to the research lab then back to the patient. To carry out this kind of work, many medical centers will need to organize new types of care teams.

“We can do the exome sequencing for an individual patient. We can develop an organoid based upon that patient’s genomic profile. We can determine how that organoid responds to intervention and then choose the best treatment for that patient,” Naren says. “It is not common to see all the specialized expertise needed to achieve this all in one place. It takes a whole series of researchers, specialist physicians, nurses, network analysts and other support personnel all working together to help an individual get better.”