Genes aren’t always destiny. In recent years, doctors and scientists have made remarkable progress against cystic fibrosis, a fatal recessive genetic disorder that has remained stubbornly common through the centuries. Just a couple of generations ago, patients with cystic fibrosis had little hope of reaching adulthood. Thanks to improvements in treatment and management, people with the disease are starting families and reaching middle age and beyond. The ongoing revolution in gene-based therapies could buy patients even more years — and give them new reasons to make long-term plans.
Here’s an update on the disease.
Advances in medication and disease management have dramatically improved the prospects of people with cystic fibrosis. In the United States, an infant born with the disease can now be expected to live more than 40 years. Life expectancies in Canada are up to 10 years longer, perhaps in part because patients in that country are more likely to receive lung transplants.
CF at a glance
People with cystic fibrosis have inherited two faulty versions of a gene for CFTR, a protein needed for special channels that remove chloride ions from cells. Chloride ions control the flow of water throughout the body, including the water that normally keeps mucus thin and slippery. When chloride ions are trapped in cells, the mucus outside the cells becomes thick and sticky. The defect, which can be triggered by any one of more than a thousand different possible mutations within the CFTR gene, leads to a buildup of thick mucus in the lungs, making them vulnerable to infection.
CF can be diagnosed through genetic testing, but it can also be found through a simple sweat test. People with CF have too much chloride in their cells, and that translates to extra chloride in their sweat. The test can be performed at any age, making it a useful screening tool for infants.
Roughly 70,000 people worldwide are living with the disease, including 30,000 in the United States. It’s the most common life-shortening recessive genetic disease among Caucasians. More than 10 million Americans are carriers for CF, which means they have one mutated version of the gene.
A person has to inherit a mutated version of the gene from each parent to develop cystic fibrosis. More than 2,000 different mutations have been identified. Of those, more than 1,000 are known to cause disease and the vast majority of cases can be traced to just a few types of defects. The exact combination of mutations that each patient carries can affect the severity of the disease and the approach to treatment.
The most common mutation, called F508del, prevents a newly built CFTR protein from reaching the cell membrane, leaving few or no channels for the release of chloride ions. Another fairly common type of mutation affects the “gating” of the protein, or how easily chloride ions can move through the channel. Even though patients with this mutation may have normal numbers of CFTR proteins at the membrane, the end result is similar: Chloride ions are trapped in the cell, upsetting the balance.
People who inherit one mutated version and one normal version are carriers — they don’t have any symptoms of CF, but they can potentially pass a mutated gene to their children. If two carriers have a baby, there’s a one in four chance that the child will be born with CF, a one in two chance that he or she will be a carrier, and a one in four chance that the baby will be completely free of CF genes.
Cystic fibrosis triggers a cascade of problems that go beyond the lungs, although the exact symptoms and their severity depend on the type of mutations that a person carries. The disease extends to the upper respiratory tract; almost all patients eventually develop sinusitis, and nasal polyps are also common. Sticky mucus can block ducts in the pancreas, an organ that makes digestive enzymes. About 90 percent of patients have trouble digesting foods and absorbing nutrients. Symptoms of poor digestion include stomach pain, bloating and greasy stools. Almost all men with CF are infertile because of blockages or absence of the vas deferens.
Patients can remove mucus from lungs by thumping on their chest or by a daily session in a vibrating vest. Inhaled medication including dornase alfa (a type of DNase) can help break down and clear mucus. Antibiotics can treat and prevent the most common lung infections. Enzyme supplements help with digestion. Anti-inflammatories can help improve lung function in some patients. Lung transplants can add years to some patients’ lives. Cystic fibrosis is the most common reason for lung transplants in people under 50, and 45 percent of patients are still alive 10 years after the operation, according to a 2017 report in the Journal of Cystic Fibrosis.
In 2012, the US Food and Drug Administration approved ivacaftor, a genetically engineered drug that binds directly to the CFTR channel. The drug is specifically designed to open up chloride channels in patients with gating mutations. It was the first treatment to target the cause of cystic fibrosis, not simply the symptoms. At first, it was approved for only one specific mutation carried by just 4 percent of patients. By May 2017, the FDA had expanded that list to include 33 mutations, and more may be approved soon. In 2015, the FDA approved a treatment that combines ivacaftor with lumacaftor, a genetically engineered drug that helps recruit more CFTR proteins to the cell membrane. It is approved for patients over age six who inherit two copies of the common F508del mutation.
In 2017, the Cystic Fibrosis Foundation invested $3 million to study a new approach: gene therapy that uses harmless viruses to deliver functional CFTR genes into cells, offering a potential long-term fix. The main challenge will be finding a way to deliver and incorporate genes into enough cells to make a noticeable difference in symptoms. If gene therapy works at all, it should work on all types of mutations. A California-based biotech company, 4D Molecular Therapeutics, plans to use the money to complete preliminary lab studies before requesting FDA approval for human trials.