Cystic Fibrosis Treatment Research

By: Sahasra Krishnaswamy

Background

Cystic Fibrosis (CF) is a homozygous recessive genetic disorder that is commonly found in one in 3,900 newborns in America. To inherit CF, a person needs to inherit 2 copies of the mutated gene (NIH, 2024). Almost 89,000 people have CF worldwide, and 31,450 of those reside in the U.S.. A majority of the individuals with CF (91.4%) are white (Ong & Ramsey, 2023). Both the U.S. and the European Union (EU) have similar prevalence, 7.97 per 100,000 and 7.37 per 100,000 respectively (Ong & Ramsey, 2023).   This disorder is relatively rare, due to it being autosomally recessive, meaning the disease skips a generation or two before reappearing. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is the gene that is mutated in CF. This gene is in the middle of chromosome 7 in humans, and it encodes for the CFTR protein (Britannica, (n.d)). This protein encodes for the regulation of the flow of salt and fluids in and out of the cell. It also controls chloride regulation. Mutations to the CFTR gene can cause it to not work properly, or not be there at all. This causes a thick mucus to build up in the lungs, which causes infections, as well as complications in the pancreas. The most common mutation of the CFTR protein is the deletion of phenylalanine 508 (F508del) (Ong & Ramsey, 2023). This mutation is present in about 70% of people with cystic fibrosis (John Hopkins, 2024). 

Cystic fibrosis symptoms vary on the affected organ as well as the severity of the disease.  Most symptoms usually occur in the lungs, the most affected organ of this disease. The mucus that is created due to the mutated CFTR gene clogs the bronchioles of the lungs, or the tubes that transport air through the lungs (Mayo Clinic, 2024). This can cause symptoms such as a persistent cough, repeated lung and sinus infections, and a limited ability to do physical activity. In some patients, CF also affects the digestive system. The same thick mucus that affects the respiratory system, or the organs that allow breathing, also affects the digestive system, the organs that help  digest food. The mucus blocks the digestive tract that brings digestive enzymes from the pancreas to the intestines. Digestive enzymes help break down the food into more easily absorbable sizes, and without it, the intestines will not completely absorb the nutrients from food (Mayo Clinic, 2024). Some digestive symptoms include foul smelling stools (poop), severe constipation, as well as poor weight gain and growth (Mayo Clinic, 2024). 

It is common for people to get screened for cystic fibrosis as a newborn or infant. In fact, every state in the U.S. requires mandatory screening for CF when a child is a newborn (Mayo Clinic, 2024). A newborn can be screened in many different ways, but the most popular include a sweat test, genetic testing, and blood tests. Sweat tests are the only way to confirm and diagnose CF, however, other forms of screening can be used in addition to a sweat test to confirm results (Cystic Fibrosis Foundation, (n.d.)). Sweat tests are usually performed on a 2 week old baby. A sweat test tests for the amount of chloride present in the sweat. This is because in CF, a person has too much salt in their sweat. In this test, a colorless and odorless chemical called pilocarpine is placed on an area of skin along with some electrical stimulation (Cystic Fibrosis Foundation, (n.d.)). Results from this test are sent to a lab, where they will determine if a child could have CF. A child with a chloride level of 60 mmol/L or greater most likely has CF (Cystic Fibrosis Foundation, (n.d.)). In genetic testing, professionals look for specific changes on the CFTR gene to confirm cystic fibrosis. In blood testing, a professional draws a sample of blood and tests for high levels of a chemical called immunoreactive trypsinogen (IRT) (Mayo Clinic, 2024). The pancreas release IRT, and may show that a child has CF. However, IRT could be released because of a stressful delivery or premature birth, which is why it is used alongside other more reliable tests. 

While cystic fibrosis cannot be cured, there are many treatments that make living life much easier. One of the most common treatments are CFTR protein modulators. These treatments attempt to correct the mutated protein (Cobb et al., 2024). There are two main types of CFTR modulators available: CFTR potentiators and CFTR correctors. CFTR potentiators improve the chloride flow in the cell membrane, and CFTR correctors help the CFTR protein to form its normal 3D shape. There is a third CFTR modulator that is currently being developed, called CFTR amplifiers. The amplifiers help increase the production of the CFTR protein. Currently, there are 4 types of modulators available to the public. These are: Ivacaftor (Kalydeco), lumacaftor/ivacaftor (Orkambi), tezacaftor/ivacaftor (Symdeko), and elexacaftor/tezacaftor/ivacaftor (Trikafta) (Cobb et al., 2024). Another alternative to the CFTR modulators are antibiotics. Antibiotics are very effective in treating lung infections that come with CF (Gale, 2012). While it is effective, it isn’t guaranteed to work, as the antibiotics target bacteria that is embedded in the mucus. The large bacterial population, also known as biofilms, are highly resistant to these antibiotics (Gale, 2012). Because of this, many patients rely on drugs as their treatment. One of these drugs are bronchodilators. This drug is inhaled, and it helps increase the amount of air inhaled by expanding the small air pockets in the lungs (Gale, 2012). Another type of drug called pulmozyme (dornase alfa) supplies an enzyme called dornase. This enzyme helps thin out the thicker mucus, allowing for the mucus to be coughed up easier. This provides temporary relief for CF patients (Pulmozyme, 2025). Some patients also use airway clearance, or chest physical therapy, to help with CF (Mayo Clinic, 2024). This helps get rid of the mucus in the airways, and it helps get rid of infections and inflammation as well (Mayo Clinic, 2024). 

While these treatments help CF patients go about their day to day life, it is important to live a healthy lifestyle to limit the symptoms and difficulties of living with CF (Mayo Clinic, 2024). CF limits the amount of nutrients that are absorbed by the intestines, therefore, it is important to pay attention to diet and nutrition in order for the body to receive the nutrients it needs. Health specialists also recommend taking pancreatic enzyme capsules in order for the enzymes to reach the small intestines (Mayo Clinic, 2024). People with CF also benefit from exercise, as it helps loosen up the mucus in the airways. Additionally, it is important to stay away from smoking, because it affects the weakened lungs. In addition to that, it is important to practice good hygiene, such as hand washing, as it protects against infections (Mayo Clinic, 2024).

Scientific Study

The purpose of this scientific study is to find the most effective treatment that helps most people with CF. This study determined that CFTR Modulators are the most effective treatment. It also sought to determine which CFTR modulators were the most effective. The experts who conducted this study searched the website PubMed for studies of practical guidelines, meta-analyses, and clinical or randomized clinical trials of cystic fibrosis (Ong & Ramsey, 2023). The time frame of these studies was from January 1, 2012 to December 31, 2022, but it was updated to March 31, 2023. From this, over 1,000 articles were retrieved. After the retrieval of these articles, another search was conducted from January 1, 2022 to December 31, 2022, focused on CFTR modulators (Ong & Ramsey, 2023). This search resulted in 26 more studies. From the retrieved studies, the reference lists were manually searched for more relevant sources. 

The authors of this study gave high priority of inclusion to the sources that were meta-analyses, randomized clinical trials, and studies about general practices (Ong & Ramsey, 2023). Ivacaftor was the first CFTR modulator tested in a randomized clinical trial, and was effective, however, it only benefited the small number of people who had a different variant of the CFTR gene mutation (Ong & Ramsey, 2023). The trial also showed that people with two copies of the F508del variant needed a combination of  CFTR corrector and potentiator medications. Another randomized clinical trial showed that the CFTR correctors lumacaftor and tezacaftor combined with ivacaftor improved the state of people homozygous (people who have two of the mutated gene) for the F508del variant (Ong & Ramsey, 2023). Another clinical trial studied the combination of a second-generation corrector, elexacaftor, with the first-generation tezacaftor, along with the potentiator, ivacaftor. Together, these three CFTR modulators improved respiratory symptoms for people who were homozygous for the F508del variant (Ong & Ramsey, 2023). 

In a randomized clinical trial, around 400 patients who were heterozygous (people who have one copy of the gene) for the F508del variant were given elexacaftor-tezacaftor-ivacaftor. These people experienced improved respiratory symptoms and a decrease in sweat chloride concentration (Ong & Ramsey, 2023). The combination of Exacaftor-tezacaftor-ivacaftor (Trikafta) is approved for patients who are of age two or older. Approximately 90% of people benefit from this combination of CFTR modulators (Ong & Ramsey, 2023). While Trikafta is beneficial for many patients, it is not easily accessible for many people, as prices of CFTR modulators range from $272,623.00 to $311,741.00 per year. This review, while informative, has limitations. Relevant publications may have been missed when searching for studies and articles. Second, COVID-19 and other diseases were not taken into consideration while researching CFTR modulators (Ong & Ramsey, 2023).

Closing & Relevance of Continued Study

This study focused on the most effective CFTR modulators. The authors who conducted this study found that the most effective CFTR modulator was Trikafta (Ong & Ramsey, 2023). The findings from this study can help improve future CFTR modulators to be effective for all people with different variations of the CFTR gene mutation. Promoting the study of CFTR modulators can help reduce mortality rates, as well as improve medications for children and adults who suffer from this disease (Ong & Ramsey, 2023).

References

CFTR. Johns Hopkins Cystic Fibrosis Center. (2024, June 14). https://hopkinscf.org/knowledge/cftr/#:~:text=More%20than%202500%20different%20mutations,F%2C%20in%20the%20CFTR%20protein.

Cobb, Bryan., Scogna, Kathleen., & Lerner, Lee. K. (2024). Cystic fibrosis. Gale. https://link.gale.com/apps/doc/GTRMEV543054032/SCIC?u=va_s_316_479&sid=bookmark-SCIC&xid=502ba0c5

Cystic Fibrosis Foundation. (n.d.). CF Genetics: The basics. Cystic Fibrosis Foundation. https://www.cff.org/intro-cf/cf-genetics-basics#:~:text=Cystic%20fibrosis%20is%20caused%20by,other%20parts%20of%20the%20body. 

Cystic Fibrosis Foundation. (n.d.). Sweat test. Cystic Fibrosis Foundation. https://www.cff.org/intro-cf/sweat-test 

Encyclopædia Britannica. (n.d). Cystic fibrosis (CF). Britannica School. https://school.eb.com/levels/high/article/cystic-fibrosis/28436

Gale. (2012). Cystic Fibrosis Drugs. https://link.gale.com/apps/doc/RZBMZS176140361/SCIC?u=va_s_316_479&sid=bookmark-SCIC&xid=e96c3712

KU Medical Center. (n.d.). Cystic fibrosis breakthrough. https://www.kumc.edu/school-of-medicine/about/ku-medicine-magazine/winter-2021/cystic-fibrosis-breakthrough.html#:~:text=Trikafta%2C%20a%20pill%20meant%20to,fibrosis%20patients%20have%20this%20mutation. 

Mayo Clinic Staff. (2024). Cystic fibrosis—Symptoms and causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700

Ong, T., & Ramsey, B. (2023). Cystic fibrosis: A review | pulmonary medicine. JAMA Network. https://jamanetwork.com/journals/jama/fullarticle/2805701

Pulmozyme. (2025, January 10). Cystic fibrosis treatment option: Pulmozyme® (Dornase Alfa). Pulmozyme. https://www.pulmozyme.com/ 

U.S. Department of Health and Human Services. (2024, November 15). What is cystic fibrosis?. National Heart Lung and Blood Institute. https://www.nhlbi.nih.gov/health/cystic-fibrosis