A new biomarker for cystic fibrosis?

A diagnosis of cystic fibrosis can mean a lifetime of struggling to breathe and ultimately an early death. But with early detection, people with the rare genetic disorder live longer and have a higher quality of life.

Currently, diagnosis relies on a sweat test that can only be performed by trained technicians and requires special iontophoresis equipment. But a new test for cystic fibrosis could help doctors detect the disease earlier in disadvantaged communities in the United States and underdeveloped countries.

“This assay could be used pretty much by any hospital in the world. The tools are rudimentary,” said Ian Thornell, a research assistant professor in pulmonary, critical care, and occupational medicine at the University of Iowa. In comparison, the sweat test can only be performed at Cystic Fibrosis Foundation-accredited centers, of which there are only 130-some-odd worldwide.

Cystic fibrosis affects an estimated 35,000 Americans, according to the Centers for Disease Control and Prevention. A defective gene called cystic fibrosis transmembrane conductance regulator (CFTR) causes sweat and mucus to become sticky and thick, resulting in clogged passageways in the lungs, pancreas, and other organs.

Scientists at Aarhus University in Denmark recently developed a urine test for the disease that requires no specialized equipment or training. The new test not only has the potential to make cystic fibrosis diagnosis easier and more accessible, but also could serve as a biomarker to track disease progression.

Publishing their work on Nov. 1 in The Annals of Internal Medicine, the researchers studied 50 adult cystic fibrosis patients before and after treatment with Kaftrio. Kaftrio is the European version of Trikafta, the newest CFTR modulator drug. CFTR modulators work by directly targeting CFTR protein defects. Before the breakthrough development of CFTR modulators in the last decade, cystic fibrosis patients relied on therapies capable only of treating disease symptoms such as bacterial infection and mucus build-up.

Prior to treatment, researchers gave the patients sodium bicarbonate (baking soda) and analyzed the amount of bicarbonate in their urine. The patients underwent this same urine test after six months of treatment with Kaftrio. The rationale behind the urine bicarbonate test is that defects in the CFTR gene inhibit the kidneys’ ability to remove bicarbonate from the body, resulting in decreased levels of urine bicarbonate excretion for cystic fibrosis patients.

Lead author Jens Leipziger and his colleagues were able to quantify the change in urine bicarbonate levels after the six-month treatment period, reporting a restoration on average to 70 percent of the bicarbonate levels seen in people without cystic fibrosis. The findings suggest the urine bicarbonate test can quantify CFTR function, making it a useful tool for measuring disease severity before and after treatment.

Leipziger explained in an email to WORLD that the new test can quantify treatment efficacy for any drug that targets CFTR. He said that Vertex Pharmaceuticals, the company that developed Trikafta, is also developing new CFTR therapies with improved features.

Dr. Jennifer Guimbellot, a scientist at the University of Alabama’s Cystic Fibrosis Research Center, agreed that the urine bicarbonate test has the potential to improve healthcare access for cystic fibrosis patients. Guimbellot thought it could likely be implemented at medical centers lacking the resources needed to perform the sweat test.

But Guimbellot and her colleague, Dr. Amit Gaggar, said the test is more applicable as a biomarker to track disease progress, as was done in the study, than as a screening tool. Gaggar mentioned a need for drugs targeting defects in CFTR that Trikafta is unable to treat. He hypothesized use of the urine bicarbonate test in, for example, a gene therapy clinical trial to easily assess how much, if at all, the treatment improved CFTR function.

Guimbellot is hopeful the new test could help patients with rare CFTR gene mutations. If the urine bicarbonate test can accurately measure CFTR function in those patients, they could be included in clinical trials that they otherwise are prevented from participating in.

Leipzinger said his team is designing a multicenter study to validate the findings of their initial study. “Great optimism exists that this novel test could prove helpful in the real world,” he said. “The test is cheap and easy to do. But we need to develop an accredited measuring device to make this test practical in each cystic fibrosis clinic.”