In the past year, there has been a personalized medicine success story- a “cure” has been found for patients with a rare cystic fibrosis (CF) mutation via the development of a drug called Kalydeco (the pronunciation is similar to “kaleidoscope”). However, a true cure for most patients with CF remains to be found. But in the meantime, there have been some exciting developments aimed at treating most patients with CF.
A nice summary of the most recent developments can be found here. I will try to give my own summary below!
Cystic fibrosis is a disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. It is a large gene, and there are many different mutations in the CFTR gene that can lead to cystic fibrosis. It is an autosomal recessive disease, meaning that someone with cystic fibrosis got a mutated CFTR gene from both their father and their mother, who are generally asymptomatic CF carriers. Cystic fibrosis is characterized by a build-up of mucus in the lungs, leading to progressive lung disease. There is also mucus clogging of the pancreatic ducts, leading to various gastrointestinal issues and malabsorption. The average life expectancy is about 37 years. Treatment for CF includes using various inhaled medicines, vibrating vests to help loosen mucus in the lungs, pancreatic enzymes to aid absorption of fats, and often antibiotic treatment for lung infections. Due to malabsorption issues, a high calorie diet is important.
An example of what it is like to care for a child with CF can be found here. Caring for a child with cystic fibrosis is almost a full-time job- they must make their children undergo breathing treatments multiple times every day, make sure they adhere to a high calorie diet, and remember to take their enzymes before eating. They must closely observe their child’s health, especially to their coughing and wheezing, and make sure to keep their child away from anyone who is sick. And they often spend a lot of time seeing doctors or being in the hospital.
There have currently been 3 new drugs developed to treat CF. The first is Kalydeco (also known as Ivacaftor), which I mentioned above. The others are Lumacaftor and VX-661.
There are various mutations that cause CF. Here is a link from the CF Foundation website on the various mutations.
The CFTR gene codes for a protein that is inserted into the apical membrane of lung and intestinal tissue, as well as the vas deferens and the sinuses. The protein’s main function is to act as a chloride channel, and it helps to maintain an airway liquid layer, which in turn helps with mucus clearance. There are five general classes of CFTR mutations. The most common mutation, F508del, is a Class II mutation, meaning that there is an issue in the processing of the CFTR protein- either it is misfolded or targeted for degradation by a proteasome, so there is not enough of the CFTR protein to prevent CF symptoms. The drug Kalydeco is meant to target the G551D mutation (Class III), though it now appears to benefit patients with Class III-V mutations. Kalydeco (Ivacaftor) is a potentiator drug, meaning that it helps the protein (chloride channel) come to the surface of the cell and carry out its functions. The other two drugs, Lumacaftor and VX-661, are CFTR correctors, meaning that they help correct the misfolding of the CFTR protein, as seen in Class II mutations. VX-661 is still quite new, but is supposed to be a similar but better version of Lumacaftor. In many clinical trials going on, both a potentiator and a corrector are given together.
Other drugs in the works to treat CF include 2nd generation modulators. One of these drugs targets sodium channels (the CFTR protein also regulates an epithelial sodium channel (ENaC)). In shutting down ENaC, for example, the water layer can be restored (the layer is too thin in CF patients, resulting in dehydrated mucus).
These CF drugs are for the most part available as part of a clinical trial. Kalydeco is extremely expensive (about $300,000 a year). Insurance is supposed to cover it in most cases. These drugs are not yet available for young children.
This is all exciting news for the CF community- CF is a difficult, lifelong disease, and hopefully treatment will be available for most patients soon, letting them live normal, long lives.
Orkambi, a combination of ivacaftor (Kalydeco) and lumacaftor, just got FDA approval for use in patients with homozygous F508del mutations! Link to NYTimes article here.