For patients with the life-threatening genetic respiratory disorder known as cystic fibrosis (CF), daily treatment routines often mean a life of inconvenience and discomfort. For UAB Medicine patient Mark Sleeper, however, CF is no longer a matter of constant care. Major advances in drug therapy at the UAB Gregory Fleming James Cystic Fibrosis Research Center gave Sleeper what he calls “a completely normal life.”
May is CF Awareness Month, and according to the Cystic Fibrosis Foundation patient registry, more than 30,000 people in the United States and almost 70,000 worldwide have the condition. Fortunately, major treatment breakthroughs at UAB Medicine and elsewhere are making life easier for people such as Sleeper, 30, who has been treated for CF for most of his life.
Sleeper says he’s lost count of the number of surgeries performed to treat or correct various conditions he’s suffered because of the disease. He does recall thinking of so many procedures as “just the way he lived,” and he always assumed that pattern would continue.
“I’ve had between 20 and 30 surgeries, most of them to treat sinus problems,” Sleeper says. “I also had my gallbladder removed. I remember as a teenager thinking that I might see a cure one day. That was around the time I started visiting the transition clinic, where young CF patients start going to appointments by themselves and learning to manage their care on their own. But at the time, I had absolutely no concept that I would enjoy a completely normal day-to-day life by age 30.”
By “normal”, Sleeper means a daily life that does not call for near-constant management of his condition. CF affects multiple organs such as the lungs, intestines, and pancreas, where thick mucus builds up and can cause lasting problems for those with the disease. Respiratory issues cause the most serious complications, and without continual care, CF patients suffer a dangerous drop in lung function.
Managing symptoms can require various physical therapies and medications that help loosen lung mucus so it can be coughed up, in order to improve breathing and reduce infections. Airway clearance techniques involve special ways of breathing and coughing, electronic therapy vests that use vibrations, and having a caregiver gently strike the chest and back.
Steroids and other medications may reduce inflammation, while antibiotics can prevent or treat lung infections – a common risk with CF. Bronchodilators are used to relax and open airways. Sinus surgery, which removes infectious material and improves sinus drainage, is sometimes necessary to treat acute sinusitis. In highly advanced cases of CF, a lung transplant is required.
Treating the Cause, Not the Symptoms
Cystic fibrosis is caused by mutations in the gene that produces the CFTR protein (cystic fibrosis transmembrane conductance regulator). Mutations in the CFTR gene can disrupt the activity of the CFTR protein, which carries chloride in and out of cells and helps regulate the balance of salt and fluids in tissue throughout the body. With compromised CFTR function, mucus becomes thick and sticky, clogging the lungs and digestive system and making it difficult to breathe. Thick mucus also can trap bacteria in the lungs, causing serious infections. In the pancreas, mucus interferes with the organ’s normal function of helping the body digest food.
Research has located almost 2,000 different CFTR mutations. Sleeper has one of the most common, known as F508del, which causes the CFTR proteins to “mis-fold” into the wrong shape and fail to reach the cell membrane. Fortunately, Sleeper had the opportunity to enroll in clinical trials at the CF Research Center. It was there that researchers were developing compounds to “repair” proteins that caused CF.
UAB Medicine’s Steven Rowe, MD, a professor in the UAB Division of Pulmonary, Allergy and Critical Care Medicine, now directs the center. He recalls the early phases of studies involving a two-drug combination therapy for CF.
“There was some anticipation during the early 1990s that gene therapy would address mutations that cause CF,” Dr. Rowe says. “But almost a decade later, the decision to repair the protein, rather than the gene, is what brought us success. It was a high-risk approach, because there are so many ways that proteins can make errors. So fixing them called for screening programs to locate the right drug combination, assuming you had a good choice of therapy drugs to start with.”
With promising choices of drugs from the pharmaceutical company Vertex, tests developed in Dr. Rowe’s lab showed which compounds were the most promising. UAB patients, including Sleeper, were some of the earliest enrollees in the groundbreaking trials of Vertex’s drug ivacaftor, the first protein-focused treatment for CF, which received U.S. Food and Drug Administration (FDA) approval in 2012.
“The first time we treated patients with ivacaftor, in a clinical trial a few years earlier, we received a call from one patient within a couple of days,” Dr. Rowe says. “She said, ‘I’m finally coughing up all this mucus.’ We knew something good might be happening.”
Although Sleeper was enrolled in certain clinical trials, “something good” would not happen for him until 2018, when Dr. Rowe and his team made yet another breakthrough in CF drug therapy.
“Therapies for CF have to be targeted to specific mutations taking place with an individual,” Dr. Rowe says. “This is the very definition of precision medicine. Mark Sleeper is a great example of a patient with a very common ‘mis-folding’ mutation, F508del, and another mutation that is extremely difficult to fix. A drug that resolves one problem of the mutation doesn’t address the others. It was an odd situation where the drug would have some effect on a patient who had two mutations and no effect on a patient with just one mutation. But when we began using two drugs together, that’s when we started to see a signal. It still didn’t address all the problems with the protein, so we moved to a three-drug regimen. The response was tremendous.”
Sleeper agrees with that description. He doesn’t refer to himself as “better”, preferring the phrase “completely healthy.”
“The medication regimen developed by UAB’s amazing work at the Cystic Fibrosis Research Center changed my life,” Sleeper says. “It’s true that, genetically, I still have CF, but I do not have the disease day to day. I don’t cough, my sinuses are clean, and there is no mucus build-up in my lungs. My lung function is at 80%, where it was once at the dangerous level of 40%. I no longer need all kinds of medications for symptoms. I’m a completely healthy person. And it’s all because I take two pills in the morning and one at night.”
Progress in the area of CF drug therapy was reported in a study published by Dr. Rowe and colleagues in the New England Journal of Medicine in October 2018. According to the report, “Highly effective therapies that target the basic defect should provide therapeutic benefits for 90% of patients with cystic fibrosis.”
“This is transformational, because these advances are changing the face of the disease for the vast majority of patients,” Dr. Rowe says. “It’s one of the more remarkable stories in modern medicine. The future will enable individualized therapy based on one’s specific CF mutation and which drugs work best in a single patient’s cells.”
Today, UAB researchers are exploring promising new ways to help patients who have rare types of CF mutations. They also hope to expand CF treatment advances to lung conditions such as asthma and bronchitis. Advances first designed for only a few thousand people with CF eventually may reach millions of people suffering from other diseases.
The UAB Adult Cystic Fibrosis Program is accepting new patients for research and clinical trials. Learn more here.