Treatment for cystic fibrosis has changed significantly in the past decade. A new class of drugs can alter the way the disease progresses in the body. Known as CFTR modulators, these medications directly impact the defective CFTR protein that causes cystic fibrosis. They can enhance or restore function in patients with this condition. The problem, however, is that these drugs don’t work for everyone.

“Between 10% to 20% of patients with cystic fibrosis have a genetic mutation that prevents them from having access to CFTR modulators,” says John Brewington, MD, a Cincinnati Children’s pulmonologist involved in cystic fibrosis research. “That means these therapies may not work for them. This group hasn’t really been studied, however, because their genetic mutations are rare.” This is where Cincinnati Children’s researchers are stepping in. They are actively involved in identifying ways to help children who fall into this category.

Identifying Effective Medications Through Theratyping

For children with cystic fibrosis, one of the most confounding and critical questions is “Will this CFTR drug work for this patient?” Cincinnati Children’s is one of 13 National Resource Centers using funding from the Cystic Fibrosis Foundation to find the answers. However, Cincinnati Children’s is the only institution using a method called theratyping. It’s a process that investigates which genetic mutations respond to certain CFTR modulators. To do this, they test various CFTR modulators on cell samples collected from patients with rare mutations, looking for any improved protein function.

“We have a two-sided goal. From the scientific standpoint, we’re continuing to learn more about the biology of these particular defects within this population,” Brewington says. “On the other side, we are generating these data and trying to get it back out to care teams so they can provide a pathway for patients to get the appropriate drugs.”

To date, his team has collected nasal swab samples from 150 patients with these rare genetic variants. Using culture media rich with antibiotics and antimicrobials, they grow the samples into two models and treat them with available CFTR modulators, as well as ones that aren’t yet on the market. Around 60 samples have responded to treatment, resulting in 40 patients getting access to effective CFTR drugs they otherwise could not use. “This is impacting patient care,” he says. “As a clinician, it’s really rewarding to see.”

Using Mouse Models to Study Genetic Variations

Genetic mutations to the CFTR protein can be tricky, making lung disease associated with cystic fibrosis develop in a variety of ways. In fact, people who have the same genetic mutation—even siblings—can develop cystic fibrosis and have very different outcomes. TGF beta is a genetic modifier that drives more severe cystic fibrosis-related lung disease. It isn’t clear how TGF beta makes lung disease worse in children with cystic fibrosis, but some patients with the disease develop airway hyperresponsiveness—the airway smooth muscle in their lungs becomes twitchy and contracts easily. As a result, they lose lung function more quickly, have more respiratory illnesses, and develop asthma-like diseases. Preliminary research indicates that TGF beta may influence this airway hyperresponsiveness. Unfortunately, right now it’s unclear which therapies are best for these patients. With funding from the Cystic Fibrosis Foundation and National Institutes of Health, Elizabeth Kramer, MD, Ph.D., co-associate director of Cincinnati Children’s Clinical Cystic Fibrosis Center, is currently using a mouse model to investigate why TGF beta creates worse lung disease. Her goal is to develop therapies that target specific defects in CFTR function.

“We want to really tailor therapies to what’s going on in a person’s body and the defects that are there,” she says. Through tests, she’s discovered mice with delta F508 mutations, the most common gene mutation linked to cystic fibrosis, who are also introduced to TGF beta develop abnormal signaling pathways in their lungs. Their airway smooth muscle develops airway hyperresponsiveness. The same thing happens in human cells.

“We’re seeing a lot of those same abnormal signaling pathways in the human cells in the dish that we’re seeing in the mouse model,” she says. “That’s a good indication that this is important. It’s something that’s probably happening in humans, and we need to better understand it to target that pathology.”

Through these models, she says, her team can identify the pathways that are involved in creating these smooth airway muscle problems. They need to go further, though, to potentially reduce the symptoms patients experience.

“We’ve identified how TGF beta drives the worsening of this defect, and we’ve identified some large pathways that are altered in cystic fibrosis,” Kramer says. “But we need to dig deeper. We need to better understand how the epithelium and the smooth muscle communicate in the lung and how that might drive pathology because nothing is in isolation in the human body.”