A Breath of fresh air for cystic fibrosis patients
It’s not often that a radical treatment for a chronic, often fatal, disease comes around. The WEEKLY takes notice when one does. Vertex Pharmaceuticals’ (Boston, MA) innovative new drug, Trikafta, promises better health to a much broader range of people with cystic fibrosis (CF) than previous treatments. This hereditary disease of the lungs and other mucus glands afflicts about 70,000 people around the globe. Passed on through one of several possible mutations in a single gene, CF involves the overproduction of mucus that clogs its sufferers’ lungs and causes premature death. Without treatment, most patients die in their 30s. CF is an orphan disease that is prevalent mainly in America, Europe, and Australia.
Until recently, strategies for treating CF focused on the management of symptoms and involved reducing the risk of lung infections through mucus-thinning medications and antibiotics. Since 2012, Vertex has won the approval of four different drugs—Kalydeco, Orkambi, Symdeko, and now Trikafta—that effectively treat the underlying cause of cystic fibrosis. However, only Trikafta promises to treat a significant majority—90%—of patients. This is because CF is caused by a number of different mutations, and different drugs target different mutations.
This WEEKLY looks at how Vertex’s game-changing new drug targets multiple mechanisms behind the disease.
A Protein Gone Wrong
CF hinges on one of several possible mutations in the gene that encodes the “cystic fibrosis transmembrane conductance regulator” (CFTR) protein. This protein controls the production of sweat, digestive fluids and mucus. CFTR is classified as a channel protein—which creates a passage across the cell membrane. These paths allow molecules which otherwise couldn’t to pass through cells. In the case of CFTR, negatively-charged chloride ions rely on CFTR to exit cells. If CFTR doesn’t function correctly, the chloride ions build up inside. The pileup affects the fluid balance of tissue, resulting in the thick mucus that characterizes the lungs of CF patients. This mucus makes them vulnerable to potentially fatal infections.
CF is an autosomal recessive disorder. If someone has one functioning copy of the CFTR gene, they are “carriers” who won’t get the disease. People with a copy of the malfunctioning gene from each parent, in contrast, inevitably develop the illness. And while CF is always caused by a genetic flaw, many possible mutation combinations are associated with the disease.
The mutations come in two classes. The first group consists of those that lessen the quantity of CFTR proteins reaching the cell surface. The second group reduces the functioning of the proteins reaching the cell surface. Drugs that work by assisting CFTR to fold correctly and reach the cell surface are CFTR correctors. Drugs that enable CFTR to function correctly once it reaches the cell surface are CFTR potentiators. (Article continues below)
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Trikafta: Triple CF Threat
The new CF drug, Trikafta combines three small molecule drugs:
- Kalydeco, first approved in 2012, was the first CF remedy to treat the underlying cause of the disease. Kalydeco binds to the misfolded CFTR protein and increases its ability to remain open and function on cellular surfaces—a CFTR potentiator. Although highly effective, the drug only works in approximately 10% of CF patients. Kalydeco alone doesn’t help patients whose mutation prevents CFTR from reaching the cell surface.
- Tezacaftor and elexacafter, the other components of Trikafta, target the most common CF mutation. This is a single amino acid deletion in the CFTR protein responsible for two-thirds of CF cases. This mutation results in a protein so misfolded, it never makes it to the cell surface. Tezacaftor and elexacafter are CFTR correctors. They bind to and stabilize the misfolded proteins so they can travel to the cell surface. Once there, Kalydeco kicks in and improves the function of CFTR.
Term of the Week: Chaperone Protein
Chaperone proteins assist in the correct folding and assembly of other proteins. Many of the proteins we produce require chaperone proteins to ensure their correct molecular structure.
A pharmacological chaperone is a small molecule drug that works on specific misfolded proteins and encourages them to fold correctly. Tezacaftor and elexacafter are pharmacological chaperones.
The leap from simply managing CF to attacking its roots shows the amazing potential of drug development, highlighting biotech innovation at its best.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.