A new approach to treating cystic fibrosis (CF) is offering hope for more personalized and effective care, particularly for children. Researchers at UNSW Sydney are growing “mini-me” organs – tiny replicas of a patient’s lungs or gut – from their own cells to predict how they will respond to different medications. This innovative technique promises to move beyond a one-size-fits-all approach and tailor treatments to the unique genetic makeup of each individual with CF.
Understanding Cystic Fibrosis
Cystic fibrosis is a genetic disease that affects multiple organs, primarily the lungs, gut, pancreas, and liver. It’s caused by mutations in the CFTR gene, which regulates the flow of salt and water in and out of cells. Associate Professor Shafagh Waters, a stem cell and regenerative medicine researcher at UNSW, explains the issue to young patients using a simple analogy: “I tell them to picture an airport,” she says. “There’s a gate at the surface of every cell. It’s meant to open so water and salts can flow through—just like planes leaving a gate. In cystic fibrosis, that gate might be stuck closed, built in the wrong place, or it could be so unstable that it falls apart as soon as it forms.”
When the CFTR protein doesn’t function correctly, mucus becomes thick and sticky, leading to chronic inflammation and recurrent infections. This buildup obstructs airways in the lungs and digestive tracts, causing breathing difficulties and digestive problems. In Australia, two people die from the disease every four weeks.
The Challenge of Genetic Complexity
More than 2,000 different mutations in the CFTR gene have been identified, each potentially affecting the severity of the disease and the response to treatment. Current CFTR modulator drugs are designed to address specific types of defects, but even patients with the same mutation can respond differently to the same medication. This variability has made CF a compelling model for personalized medicine.
A/Prof. Waters notes the complexity: “When I first started, I thought, ‘I only have one gene to deal with. How difficult can a monogenic disease be?’ The reality is, although this is one gene, it’s very complex and the patients are very heterogeneous in the way that they present. If I give you 100 patients with the same mutation and we give them the same medication, perhaps 40% respond. Some of them don’t respond. And some of them actually get worse.”
Organoids: “Mini-Mes” for Personalized Treatment
To address this challenge, A/Prof. Waters’ lab developed a method to grow organoids – three-dimensional, miniature versions of a patient’s lungs or gut – from their own stem cells. These “mini-mes,” as A/Prof. Waters calls them, can then be tested in the lab with different CFTR modulator drugs to determine which one is most effective for that individual patient.
Recent research, published in Thorax, demonstrated the potential of this approach. The team took nasal cells from 24 children, aged five to 17, and created lung organoids for each. They then exposed each organoid to all four currently available CFTR modulators and compared the lab results to the children’s real-world clinical responses, including lung function and sweat chloride levels.
The study found a strong correlation between the organoid responses and the clinical outcomes, supporting the use of organoids as a reliable way to predict which children are most likely to benefit from specific CFTR modulators.
Successful treatment causes the organoids to swell as chloride and water move through the restored CFTR protein, a visual sign of function. A/Prof. Waters describes this as “dancing organoids.”
Bridging the Gap to Clinical Practice
While organoid testing is already used in some countries to guide treatment decisions, Australia currently lacks a standardized pathway for its implementation. Professor Adam Jaffe, a respiratory pediatrician at UNSW, emphasizes the need to integrate this technology into the clinical system. “This test needs to be delivered through the clinical system, with standardized, reproducible results just like any other accredited pathology assay,” he says. “A doctor should be able to request this for an individual, so we know what drugs they respond to.”
The benefits of personalized organoid testing are significant. It could reduce the time patients spend on ineffective medications, optimize the use of expensive therapies, and provide a more precise understanding of each child’s individual needs. For patients whose current drugs are not working, this testing could spare them months of treatment with no benefit.
A/Prof. Waters believes that cystic fibrosis, with its genetic complexity, is an ideal starting point for personalized medicine in Australia. She hopes that the recent study will build confidence in the clinical community and pave the way for widespread adoption of organoid testing as part of standard CF care within the next few years. “Models like these give us the power to truly personalize therapy and give every child their best chance.”
Recent updates in newborn screening, as reported by Ann & Robert H. Lurie Children’s Hospital of Chicago in partnership with the Cystic Fibrosis Foundation and the CDC, show progress in early diagnosis, with 67% of infants screened within the first 28 days of life in 2024, compared to 60% in 2014. However, approximately one-third of infants are still diagnosed later than optimal, and false-negative results remain a concern, particularly among Black and Asian infants.
