The long breath: Medical advancements giving cystic fibrosis patients a fuller life

Cystic fibrosis (CF) is a genetic disorder that causes the body to produce thick, sticky mucus that builds up mainly in the lungs, clogging the airways and trapping bacteria. As a result, people with CF experience persistent cough, shortness of breath, recurrent lung infections,  chronic inflammation, and progressive lung damage.

The mucus can also build up in the pancreas and block the ducts that carry digestive enzymes, making it difficult to absorb nutrients from food and often causing diabetes due to damage to the insulin-producing cells .

Similarly, mucus buildups in the intestines contribute to poor digestion, for which CF patients often have difficulty gaining weight.

The disorder was first described by American physician Dorothy Hansine Andersen in 1938. At the time, life expectancy for CF patients was only six months.

Nowadays, more than half of CF patients make it into adulthood .

While there’s a lot of variability in life expectancy based on factors like the specific CF gene mutation, access to care, and overall health, it is estimated that CF patients can currently live into their mid-40s , with some sources estimating that half of babies born with CF between 2019 and 2023 will make it into their 60s.

The reason? A combination of groundbreaking medical advancements, from medication development to new diagnostic methods, treatment devices, and more.

From post-mortem diagnosis to newborn screening

In the 1930s, CF diagnosis was made post-mortem through autopsies of babies who died of malnutrition.

Then, in 1953, physician and researcher Paul di Sant’Agnese identified an increased salt content in the sweat of CF patients, leading to the development of the sweat test in 1959.

The sweat test stimulates the sweat glands by applying pilocarpine and a mild electrical current directly to the arm or leg. After stimulation, sweat is collected and analyzed in the lab for chloride levels.

People with CF typically have higher chloride levels in their sweat due to a malfunctioning CFTR protein, which affects the movement of chloride ions across cell membranes.

Although these details were not known at the time, the sweat test gained widespread use as a reliable diagnostic tool for CF.

In the 1980s, the discovery of the CFTR gene and mutations that cause CF further solidified the role of the sweat test in confirming the diagnosis and paved the way for genetic testing , allowing for definitive diagnosis even in newborns.

Current newborn screening programs usually involve testing infants shortly after birth for elevated levels of immunoreactive trypsinogen (IRT), a chemical made by the pancreas that is usually found in high levels in babies with CF.

If the initial screening indicates a potential risk for CF, the sweat test must be conducted. If the sweat test is inconclusive, genetic testing might be advised.

Early diagnosis has proved to maximize survival in CF patients by many studies.

Breakthroughs in medication

1. Antibiotics

The introduction of antibiotics in the 1940s allowed for more effective treatment for CF-induced lung infections, reducing mortality rates related to them.

Sulphonamides and nebulized penicillin became the backbone of treatment for CF. However, frequent infections caused antibiotic resistance, diminishing their effectiveness over time.

The median age of survival remained low, with 67% of patients not reaching 7 years . The development of other types of antibiotics during the 1950s helped raise this number.

In the 1970s and 1980s, IV antibiotics were used to control chronic lung infections. Having identified the pathogen that most commonly causes these chronic lung infections in CF patients, scientists started developing inhaled antibiotics to treat them.

This is because inhalation allows for higher concentrations of these drugs to be delivered directly to the lungs, on a regular basis, without exposing the patient to the side effects associated with frequent intake of oral antibiotics.

The FDA approved an aerosolized form of tobramycin, one of the most effective antibiotics against Pseudomonas , in 1997.

Parallelly, during the 1980s, various compounds had been investigated for their ability to reduce mucus viscosity and improve airway clearance.

In 1993, dornase alfa, the first specific mucus-thinning agent for CF, was approved by the FDA. This drug helps relieve mucus obstructions and prevent infections in the respiratory tract by making patients eliminate mucus in their cough .

2. Nutritional support

Malnutrition, due to impaired nutrient absorption, is a common complication of CF. When thick mucus blocks pancreatic ducts, the pancreatic enzymes that break down fats, proteins, and carbohydrates cannot reach the small intestine.

As a result, approximately 85% of CF patients are diagnosed with Exocrine Pancreatic Insufficiency (EPI) and treated with pancreatin, a mixture of pancreatic enzymes of porcine origin that comes in capsules.

This is called Pancreatic Enzyme Replacement Therapy (PERT) and is usually combined with vitamin supplements and special diets .

3. CFTR modulators

Initially, CF was thought to be caused by nutritional deficiencies, persistent infection, and many others —until in 1989, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7, were found to be the cause of CF. More than 2,500 CF-causing mutations have been discovered since then.

The CFTR gene provides instructions for making a protein called CFTR. This protein acts as a channel that transports negatively charged particles called chloride ions in and out of cells. This transport of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, slippery mucus that flows easily.

When the CFTR gene fails to produce the CFTR protein, or the protein is defective or insufficient, it leads to the CF-causing thick mucus.

Knowing this, in the early 2000s, researchers began to look for treatment options that addressed the root cause of CF, leading to the creation of CFTR modulators in the 2010s.

CFTR modulators are a class of medications that enhance the function of the CFTR protein in different ways:

• Potentiators: This type of CFTR modulator helps open the CFTR channel that is present at the cell surface, allowing chloride ions to flow more freely. This is particularly effective for patients with specific gating mutations that prevent the CFTR protein from opening properly.
  
• Correctors: Many CF mutations cause the CFTR protein to misfold. To target these mutations, medications like Lumacaftor (Orkambi) and Tezacaftor (Symdeko)  were developed to help the CFTR protein fold correctly and reach the cell surface so that it can work effectively.
  
• Combination therapies: The most advanced treatment, Elexacaftor/Tezacaftor/Ivacaftor (Trikafta), combines both potentiators and correctors to maximize CFTR function.

CFTR modulators marked a turning point in CF treatment, but they are only effective in patients with specific mutations.

Treatment devices

Chest physiotherapy (CPT) has long played an important role in the respiratory management of CF.

CPT involves the use of manual techniques like clapping, vibration, and postural drainage to loosen mucus.

Nowadays, CPT is usually combined with medical devices that aid with airway clearance.

For example, many CF patients use Positive Expiratory Pressure (PEP) devices, which typically consist of a mouthpiece or mask connected to a valve that provides resistance during exhalation. This resistance creates positive pressure in the airways, pushing air behind mucus to help detach it from lung walls.

Oscillating PEP devices, on the other hand, not only create resistance but also produce vibrations to loosen the mucus.

Similarly, the oscillating vest utilizes High-Frequency Chest Wall Oscillation (HFCWO) technology to create vibrations in the chest wall and help mobilize mucus in the lungs, making it easier to cough up.

“The Vest” is literally an inflatable vest connected to a machine that rapidly inflates and deflates the garment, generating these vibrations. First developed in the 1990s, there are currently many models available —and they are increasingly becoming more portable.

While these devices are expensive, they are covered by most insurance plans , at least in the U.S.

Gene therapy and the future of CF

Since the discovery of the CFTR gene in 1989, researchers have explored the possibility of curing CF with gene therapy.

Gene therapy consists of delivering a healthy copy of the CFTR gene to the lung cells of CF patients so that their bodies can produce normal CFTR proteins, starting from the lungs, which are usually the most affected organ in CF.

The problem is that scientists haven’t found a way to do this safely and effectively.

One of the most commonly used methods for gene delivery is based on modified viruses.  In this method, the virus’s genetic material is removed and replaced with the CFTR gene. The modified virus is introduced into the body, and then it “infects” cells with the new genetic information —the set of instructions to produce the CFTR protein.

Viral vectors, however, often struggle to achieve sufficient gene expression levels in the target cells. At the same time, they must be carefully engineered to minimize the risk of an immune response, which could cause side effects or loss of effectiveness (if the immune system detects the viral vector as foreign and neutralizes it).

Gene therapy can also be performed with non-viral vectors, such as nanoparticles and liposomes, but lung cells are hard to reach even in healthy people, as these cells are usually covered by mucus. CF patients have thicker mucus, making the task more difficult.

There’s also a risk of unintended genetic changes, particularly in integrating gene therapy , which permanently inserts genes into the cell’s DNA.

Non-integrating gene therapies deliver the therapeutic gene without altering the host genome. It is safer, but as the cells divide, the extra gene might be lost, requiring re-administration to keep up with the CFTR protein production. And gene therapy is too expensive to be repeated each time this happens.

This is why gene editing is also considered a potential cure for CF . Gene editing involves repairing the gene in situ instead of replacing it with a “healthy copy”.

CRISPR gene editing tools can technically locate the mutated CFTR gene, break it, and provide DNA-based instructions for the cell’s natural repair mechanism to correct the mutation as it kicks in to fix the broken CFTR gene.

Prime editing, a more advanced form of gene editing, has recently managed to correct CF mutation in human lung cells.