Patients with the life-threatening genetic disease Cystic Fibrosis (CF) produce thick and sticky mucus that can clog passages and cause infections and other complications in the lungs, pancreas, liver and sweat glands. The progressive disorder often makes it difficult for patients to live a normal life, with even the most stable patients requiring about two hours of daily treatment.
"It's a struggle for these patients to participate in normal daily activities such as school, work and social activities, while carrying the burden of a chronic disease requiring extensive daily treatment," explained Thomas G. Keens, MD, director of the Cystic Fibrosis Care Center at Children's Hospital Los Angeles.
In 1989, scientists identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene as the cause of CF. The CFTR protein functions as a channel for the movement of chloride ions in and out of the body's cells.
"In the lungs, for example, airway cells normally pump chloride into the airway, water follows to hydrate or thin mucous and creates a fluid layer for cilia to beat," Keens said. Cilia are hair-like structures that beat together to move mucus in the airway toward the large airways.
For a person who does not have CF, mucus can be coughed out when it reaches the large airway. In patients with CF, however, the CFTR protein does not function. Because chloride and water are not pumped into the airway, the mucus is thick and hard to cough up. Additionally, there is no fluid layer for cilia to work in, so mucus is not moved into the large airway. Thick mucus clogs airways and traps bacteria, resulting in chronic lung disease and lung damage, according to Keens.
Abnormal CFTR also affects the function of the pancreas, liver and sweat glands. For patients with CF, the pancreas produces thick digestive enzymes that fail to move into the intestines, as they should. These patients are unable to independently digest food, and therefore, suffer from malnutrition. About 85% of patients need to take pancreatic enzyme replacement therapy (PERT) in order to digest food.
According to Keens, some patients develop liver disease when biliary secretions are too thick to travel from the liver to the intestines. About 5% of CF patients develop cirrhosis, or destruction of the liver.
Normal sweat gland produce a lot of sweat, most of which is reabsorbed into the body before it gets to the skin. In CF, abnormal CFTR prevents reabsorption of sweat. CF patients sweat more, and have more salt, specifically chloride, in their sweat. The diagnostic test for CF measures the chloride concentration in the patient's sweat.
Promise of CFTR Modulators
CFTR modulators, a new class of medications that target specific defects caused by mutations in the CFTR gene, offer a great deal of hope for patients with CF. CFTR modulators are classified into three main groups: potentiators, correctors and production correctors.
"CFTR modulator medications have the promise of dramatically improving the function of CFTR at the very basic level of the disease's cause," Keens said. "Some of these CFTR modulators may also serve as a paradigm for the treatment of other genetic disorders."
Vertex Pharmaceuticals Inc.'s Kalydeco (ivacaftor) is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. The CFTR potentiator is designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.
"Proteins are the building blocks of the body," Keens shared. "Abnormal protein will not function properly because it doesn't have the right shape." CFTR modulators are chemicals that combine with the abnormal CFTR protein to rebalance charges and reshape the CFTR protein into a more normal shape.
Unfortunately, there are nearly 2,000 mutations of the CFTR protein. "CFTR modulators will have to be mutation specific, or at least groups of mutations specific, as different mutations will require a different chemical to balance charges," Keens said.
Kalydeco is FDA approved to treat CF patients with the G551D mutation and similar gating mutations. "In these mutations, there is enough CFTR on the cell membrane, but it does not work well," Keens said.
CFTR potentiators improve the function of abnormal CFTR on the cell membrane. Kalydeco has been shown to improve lung function, increase nutritional status, decrease sweat chloride, and improve quality of life in patients with these CFTR mutations, which cause CF in about 5% of CF patients.
"Other CFTR mutations are more severe, and the abnormal CFTR protein is stuck in the cell and does not get to the cell membrane," Keens relayed. Other CFTR modulator medications, called correctors, help to move, or traffic, abnormal CFTR to the cell surface.
The most common CFTR mutation is the F508del mutation, and about half of CF patients are homozygous for this mutation. Recent studies have shown that a combination of a corrector (Lumicaftor) and a potentiator (Ivacaftor) can improve lung function, nutrition, and quality of life in CF patients with the F508del mutation, shared Keens. This combination of medications may be approved by the FDA for treatment of these CF patients this year.
Another group of CFTR mutations, called missense or nonsense mutations, are under investigation with PTC Therapeutics' Ataluren. "These mutations don't make any sense as the protein string of amino acids is being formed, so the process stops short of building the complete protein," Keens shared. "These are severe mutations, in that CFTR is not made at all."
Ataluren works by telling the genetic machinery to ignore that abnormal RNA, and keep building the protein, according to Keens. The medication is currently in clinical trials for patients with these mutations and has the potential to treat 1% to 2% of CF patients.
The Cystic Fibrosis Care Center at Children's Hospital Los Angeles is a member of the Therapeutic Development Network (TDN) of the Cystic Fibrosis Foundation. The TDN consists of 77 CF Care Centers around the country who participate in multi-center clinical trials. The center was a clinical site for the F508del and Ataluren studies, and will participate in the study of VX661, a new corrector for some CF patients.
According to Keens, clinical trials are being conducted on medications to improve the treatment of CF, though they do not necessarily work at the level of improving CFTR function. "One such trial is a medication which may improve the airway surface fluid layer, so that cilia can function," he said.
Additional CFTR modulators are being developed and will be studied in clinical trials. "Scientists are striving to find medications which cause the best improvement in lung function, nutrition, and quality of life," Keens said. "There is great hope for people with CF."
Rebecca Mayer Knutsen is on staff at ADVANCE. Contact: firstname.lastname@example.org