Genetics & New Therapies for Cystic Fibrosis
By Cassandra Heald, Angelique Mercier, Vera Shively and the Genetic Counseling Team at Lurie Children’s
Late last year, the Food and Drug Administration (FDA) approved a breakthrough therapy that could help about 90% of patients with cystic fibrosis. Years of research on the genetics of the disorder helped to advance the development of this new treatment.
What Is Cystic Fibrosis?
Cystic fibrosis (CF) is a genetic disorder that can impact your breathing and growth. It is characterized by a buildup of thick, sticky mucus that can damage multiple organs in the body. Its effects can be especially severe in the lungs and digestive system. Respiratory symptoms include frequent cough, lung infections and shortness of breath. Problems in the digestive system can cause frequent greasy stools. Digestive issues can rob the body of nutrients, leading to poor growth. Males with CF typically experience fertility problems.
What Causes It?
CF is caused by genetic changes (sometimes called mutations) in a gene called cystic fibrosis transmembrane conductance regulator, or CFTR. This gene provides instructions for making a product needed by our bodies to move chloride ions, a component of salt, into and out of our cells. A balanced flow of chloride ions is key to making mucus that is thin and runs easily. This mucus provides lubrication to our airways, the lining of our digestive tract, as well as other organs and tissues. In CF, the flow of chloride ions is impaired, leading to a thick mucus that clogs and damages many areas of the body.
Genetic disorders like CF are inherited. Genes usually come in pairs, and we receive one copy of a gene from our mother and one copy from our father. CF is a recessive genetic disorder and occurs when a child inherits two genetic changes in the CFTR gene, one from each parent. If two healthy parents have a child with CF, this means that both parents are CF carriers. Carriers have one normal working copy of the CFTR gene while their other copy contains a CFTR genetic change. The working copy of the CFTR gene compensates for the copy with the genetic change, therefore, carriers do not have the condition. In addition, each parent may have a different change in the CFTR gene. When two CF carriers have a child together, that child has a one in four (25%) chance of having CF and a one in two (50%) chance of being a CF carrier. This risk occurs with each pregnancy.
How Is CF Treated?
The type of symptoms experienced, and severity of CF varies between patients. Thus, treatments are tailored to the individual. To improve lung function, a type of chest physical therapy is done to clear the airway of thickened mucus. Inhaled medicines and antibiotics are also used to treat lung infections. Pancreatic enzyme supplements may be taken with meals to aid in digestion and the absorption of nutrients.
Genetics & CFTR Modulator Therapies
Newer CFTR modulator therapies are medicines that target the gene product that does not work properly in CF. Some are approved for use in patients as young as 6 months of age. These medicines are specific to the type of gene change a CF patient has. Many different changes cause CF, so not every modulator therapy works for every patient. Currently, there are four FDA-approved modulator therapies: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), tezacaftor/ivacaftor (Symdeko®) and the newest drug, elexacaftor/tezacaftor/ivacaftor (Trikafta™).
Trikafta consists of three different modulators in one, thus it is called a “triple-combination therapy”. It was found to be effective in patients that have a least one copy of the F508del gene change, which is found in 90% of people affected by CF. It has the potential to improve the health and lives of many people affected by CF.
The Role of Newborn Screening in Early Diagnosis & Treatment
Newborn screening is a state public health service. When the baby is at least one day old, a small blood sample is collected from the baby’s heel and is used to screen for rare but serious medical conditions, including CF. These are conditions where early diagnosis and treatment can have a significant positive impact on the child’s health. In fact, for certain babies with CF, treatments may begin at diagnosis.
What Happens When a Newborn Baby Has a Positive Screen for CF?
When a baby has a positive newborn screen for CF, they should be referred to an accredited CF care center as soon as possible for follow-up sweat testing and genetic counseling. It is recommended that sweat testing occur prior to 4 weeks of age to ensure appropriate care and treatment in a baby with CF. The sweat test measures the amount of chloride in the baby’s sweat and is considered the gold standard for diagnosing CF. It is important to remember that newborn screening is only a "screen" for CF. A positive newborn screening result means that the baby might have CF and further testing is needed through the sweat test to either confirm or rule out the diagnosis. Additional genetic testing may also be completed following a positive newborn screen for CF, depending on results of the sweat test.
At Lurie Children’s, the sweat test and genetic counseling happen in a single appointment. Babies who are confirmed to have a diagnosis of CF by a positive sweat test are then seen immediately by the CF care team for initiation of appropriate treatment.