Jennifer Guimbellot in her UAB lab, where she is studying ways to predict patients' individual response to treatment based on cells collected during a simple test. Jennifer Guimbellot in her UAB lab, where she is studying ways to predict patients' individual response to treatment based on cells collected during a simple test.

Clinical trial for one: the promise of patient-derived assays

November 05, 2018
By Matt Windsor
For many patients with rare mutations, conventional clinical trials are rarely an option. But UAB researchers are creating tests using patients' own cells that could give their doctors insight on how they would respond to new therapies.

This is the fourth part of a series exploring breakthroughs in cystic fibrosis research that are paving the way for new treatments to help millions with other diseases, including COPD, asthma and more. Read part one, After cystic fibrosis 'miracle,' researchers are exploring ways to reach millions more, part two, How did we get here? Cystic fibrosis drugs go from 0-90 percent effective in a few short years, and part three, Attacking nonsense mutations in cystic fibrosis and a host of other diseases.


Even as new drug combinations bring effective therapy to more patients with cystic fibrosis, the sheer volume of CF mutations means many patients have little hope of seeing a drug company focus on their particular genetic problem.

Ivacaftor brought remarkable improvements to many of her patients, says Jennifer Guimbellot, M.D., Ph.D., a pediatric pulmonologist, assistant professor in the Department of Pediatrics in the UAB School of Medicine and a researcher in the UAB Gregory Fleming James Cystic Fibrosis Research Center. But children with rare mutations still have few good options when they fall ill.

“It’s tough to watch,” Guimbellot says, recalling two patients who barely survived harrowing exacerbations. “The parents were accepting, saying, ‘These drugs are not for my kid, and maybe they never will be.’ But I thought it was really unfair.”

Jennifer GuimbellotJennifer Guimbellot

Helping the 'lost patients'

“Those are the ‘lost patients’ in CF,” says George Solomon, M.D., a researcher in the CF Center and assistant professor in the Division of Pulmonary, Allergy and Critical Medicine. “There may never be a study that targets their mutation specifically.” The mutations in CF are so varied, the mutations so rare, and the drugs so new, that it’s often impossible to judge whether a drug will be effective in a patient with a rare mutation. And with the cost of drugs such as ivacaftor surpassing $350,000 per year, insurance companies want to see evidence to suppose a drug may work in a particular patient before they approve reimbursement.

George SolomonGeorge Solomon

The answer, Guimbellot and Solomon both say, is to develop assays from a patient’s cells that would let physicians predict that patient’s response in the lab — a personal clinical trial that can be run any time it’s needed. Solomon’s approach, using air-liquid interface cultures, has already demonstrated the viability of the combination drug Orkambi for one young patient with a rare mutation, who was referred to UAB from a hospital in New England. “They knew we were working on this, so they sent him here,” Solomon says. His tests showed Orkambi could help, and the patient’s insurance company agreed to pay for treatment. “Two years later, he’s still on the drug and doing well.”

The smart tubes

Guimbellot’s approach, which she calls nasospheroids, involves epithelial cells harvested from a patient’s nose. The cells naturally want to form a tube — “I tell patients, ‘they like to have friends,’” she says — and in a fluid-filled lab dish they spontaneously link up in a ring shape, about the diameter of a human hair, with liquid in the center. She first encountered this phenomenon in a lab at the University of North Carolina – Chapel Hill. “As soon as I saw that, I said, ‘This is something I can use,’” Guimbellot recalls.

mix guimbellot ami image 700Living nasospheroids derived from nasal cells from a patient with cystic fibrosis. The cells are stained with the fluorescent dyes calcein green and plasma membrane orange for imaging at 4x magnification. Guimbellot calls these nasospheroids AMIs, for "apical membrane in" — she also makes AMOs, or "apical membrane out" — referring to the side of the nasospheroid facing what would be the airway in the patient's body. Image courtesy Jennifer Guimbellot.


The video below shows swirling mucus and fluid inside a nasospheroid derived from nasal cells from a non-CF patient, imaged at 40x magnification. Nasospheroids derived from CF patients show little mucus and fluid movement due to dysfunctional CFTR. Video courtesy Jennifer Guimbellot.


Cells taken from healthy volunteers, with functioning CFTR channels, will move chloride in or out of the ring, and water naturally follows. In healthy people, the ring changes size based on the activity of CFTR. Cells from CF patients, lacking functional CFTR channels, don’t change size — until Guimbellot adds ivacaftor. The amount of change may be a sensitive guide to how well a patient will respond to the drug, Guimbellot has found. Especially as more new CF drug combinations reach the clinic, “I want to know if we can use these cell assays will tell me whether a patient will respond or not,” Guimbellot says.

mix guimbellot cf057 700Nasospheroids derived from nasal cells from a patient with cystic fibrosis. They are fixed (non-living), and stained with antibodies to CFTR (green areas in the image), the protein that is dysfunctional in CF patients, and Nucblue, a dye for the nucleus, at 40x magnification. CFTR is normally localized on the inner membrane, but in this CF patient the CFTR is distributed throughout the cells due to the dysfunctional localization of CFTR. Image courtesy Jennifer Guimbellot.

Nasospheroids could also help in patients with well-known mutations, Guimbellot adds. As future generations of drugs reach the clinic, these little spheroids, or their successors, could quickly tell her if any of her patients could benefit by switching to the new treatments. And she isn’t focused solely on CFTR. That’s because mutations in other genes, ones involved in drug metabolism, have an effect on how well treatments affect individual patients. The cytochrome P450 enzyme family, for instance, breaks down many types of drugs. And that means patients with active P450 enzymes may need higher doses to achieve the same effect, she says.

“You can see 20 patients with the exact same [CFTR] mutation, and they have different responses to the same drug,” Guimbellot says. “I envision a time when everyone will start on the right drug at the right dose, instead of relying on trial and error.”


Continue on to part five: From cystic fibrosis to COPD: potentiators and chronic bronchitis.