Eliminating treatment barriers with theratyping

For Alejandro Pezzulo, MD, associate professor in Pulmonary, Critical Care, and Occupational Medicine, one of the most rewarding moments in his career transpired during a phone call with a parent whose child was enrolled in one of his recent research studies.  

“I got to tell this parent that because of her kid’s sample results, her child was now eligible for life-saving treatment that insurance otherwise wouldn’t approve,” Pezzulo said. “I will never forget that phone call. That’s why we do this, right?” 

Motivated to gain experience with research that directly impacts patients, third-year medical student Ryan Gannon joined Pezzulo to study a process that may expand treatment access for people with suspected cystic fibrosis (CF) and rare gene variants. 

Their findings were recently published in Respiratory Medicine. The study demonstrates how theratyping—a process that tests drug responsiveness in a patient’s own airway cells—can provide both diagnostic clarity and a path to insurance approval for the standard of care in CF treatment: elexacaftor / tezacaftor / ivacaftor (ETI) therapy.  

Barriers to treatment
CF is caused by mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). Faulty CFTR disrupts ion transport, leading to the production of abnormally thick mucus that can clog and damage the lung’s airways.  

After decades of research, the FDA approved the first triple-combination CFTR modulator, ETI (Trikafta), in 2019. This breakthrough fundamentally changed disease trajectories for most people with CF; ETI treatment drastically improves symptoms, prevents hospitalizations, and reduces the need for lung transplants. However, about 10% of patients have CFTR variants with unestablished responsiveness to ETI. Others present symptoms highly suggestive of CF, yet their genetic testing is unclear or fails to identify a known disease-causing mutation. Those in this cohort may have CF but cannot receive a formal diagnosis, or another disease may be causing the symptoms.  

“There is this dilemma with these mutations,” Gannon said. “We don’t understand exactly how they work, or they function a bit differently than the well-known ones. So, the diagnostic criteria can become blurry.” 

More than 2,000 mutations in the CFTR gene can cause CF. However, most research and clinical trials have focused on common mutations, particularly ΔF508 (F508del), which is the most common cause of CF. After the FDA approved ETI for only this group, CF patients without this mutation remained uncertain.

Clinicians who wanted to trial modulator therapy off-label for patients faced a major barrier: cost. Without insurance coverage, treatment expenses can exceed hundreds of thousands of dollars each year, preventing clinicians and families from simply “trying the medication” to gauge its efficacy.  

“That’s when we asked, ‘Why don’t we take what we can do in the lab and use it to help these patients right now?’” Pezzulo said.  

Theratyping: A practical tool for personalized CF care  
To address the diagnostic and treatment dilemma, Pezzulo and Gannon turned to theratyping—a laboratory approach developed by the CF research community that tests how a patient’s airway cells respond to CFTR modulators.  

The first step is surprisingly simple for patients. Instead of an invasive biopsy, the research team performs a nasal brush to collect cells inside of the nose lining. In the lab, these cells are then incubated in vitro in conditions that allow them to develop into a complex cell layer that mimics the behavior of the epithelium that lines the lung’s airways.  

Once the tissue forms this functional barrier, researchers place it into an Ussing chamber, a specialized device that measures the rate of ion flux across the epithelium. Because CFTR’s main job is to transport chloride into the airways, the degree of chloride movement serves as a direct readout of CFTR function.  

“We basically isolate CFTR from all the other transporters in the cells,” Gannon said. “Then we add a drug that maximizes CFTR activity and another drug that shuts it off. The difference between those two tells us how well CFTR is working, and whether ETI can help.” 

Theratyping provides quick results, saving patients the expenses and uncertainty of a costly medication trial. It also provides individualized data, which can account for unknown gene mutations or borderline diagnostic tests. And best of all, insurance companies are responsive. When Pezzulo’s team shows that a patient’s cells respond strongly to ETI, insurers have agreed to cover therapy for a year while clinicians monitor clinical improvement. “I give the insurance companies a lot of credit,” Pezzulo said. “If it saves them and the patient money, they’ve been surprisingly flexible.”  

What makes these findings so compelling is the rapid turnaround from bench to bedside. While most lab research can take years to reach patients, Pezzulo and his team had the opportunity to help patients soon after testing.  

Purpose-driven partnership
Pezzulo points to the persistence required for patient-based research: understanding clinic schedules, ensuring consent, transporting samples across campus, and maintaining fragile cell cultures. Gannon’s leadership and organization, he said, made the project possible.  

“I learn more from working with trainees than they learn from me,” Pezzulo added. “When you surround yourself with passionate people, you can do anything.” 

Still, the most memorable payoff for the pair wasn’t the published paper or a clean set of lab results. It was in moments such as that phone call—the one Pezzulo referenced earlier—when a child with a rare CF mutation became eligible for treatment because of their data. For Pezzulo, delivering the news reinforced the urgency of the work. For Gannon, seeing a patient benefit in real-time from his lab work helped clarify his future path in medicine.  

“Watching someone start a groundbreaking treatment and then hearing how they describe feeling better at a follow-up—it was incredibly meaningful,” Gannon said. “It showed me the kind of physician-scientist that I want to be. Someone who not only learns from patients but uses the lab to help them.”  

Acknowledgements
This work was made possible by cross-campus collaboration between scientists and clinical teams such as the adult and pediatric CF clinic. Pezzulo credits Tayyab Rehman, MBBS, who helped establish the theratyping workflow before moving to Michigan, and Ian Thornell, PhD, who led electrophysiology measuring. He also acknowledges Mary Teresi, PharmD, and Jan Launspach, RN, for ensuring sample tracking, patient communication, and coordination with the hospital’s research team.