Groundbreaking research from UNSW Sydney is reshaping the future of precision medicine for genetic disorders, particularly cystic fibrosis (CF). By utilizing children’s own cells to develop miniature organ models, scientists are now able to evaluate the efficacy of CF treatments in ways previously unachievable.
Associate Professor Shafagh Waters, a prominent researcher at UNSW, emphasizes the importance of making complex medical concepts relatable for her young patients. When explaining cystic fibrosis, she invites children to visualize their bodies as airports. “There’s a gate at the surface of every cell,” she explains. “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.” This analogy effectively illustrates the challenges associated with CF, a genetic condition tied to mutations in the CFTR gene.
As A/Prof. Waters elaborates, the CFTR protein functions as a critical gatekeeper in the epithelial cells of the lungs, gut, and pancreas. Normally, this protein facilitates the flow of essential salts and water, which helps maintain mucus consistency and protects against infection. In cystic fibrosis patients, however, the malfunctioning of this gate can lead to thick, sticky mucus, causing chronic inflammation and a host of complications that affect not just the lungs but also the gut, pancreas, and liver. Tragically, two Australians die every four weeks from this disease.
The research team at UNSW has focused on personalizing treatment approaches, particularly for children with CF. By cultivating a patient’s own stem cells, they create tiny replicas of the lungs and gut known as organoids. These organoids serve as valuable testing grounds for determining which CFTR modulator drugs are most effective for individual patients.
The complexity of cystic fibrosis is underscored by the existence of over 2,000 known mutations in the CFTR gene. Each mutation can significantly influence disease severity and treatment response. While CFTR modulator drugs aim to correct specific defects—some assist in opening the gate while others help the protein reach its intended destination—patient responses can vary widely even among those with identical mutations.
A/Prof. Waters recalls her initial assumptions about the simplicity of dealing with a single gene condition. “I thought, ‘I only have one gene to deal with. How difficult can a monogenic disease be?’” she recalls. “The reality is, although this is one gene, it’s very complex, and the patients are very heterogeneous.” In practice, around 40% of patients with the same mutation may respond positively to the same medication, while others might either show no response or experience worsening symptoms.
This variability poses significant challenges, particularly when patients undergo prolonged treatments with expensive medications that may not benefit them. A/Prof. Waters’ team has pioneered organoid testing for children with ultra-rare CFTR mutations, helping those who are often excluded from clinical trials. In several instances, their research has successfully identified effective treatments that enabled these children to access therapies otherwise unavailable to them.
In their latest study, the research team sought to explore whether organoids could also predict drug responses in children with more common CFTR mutations. A/Prof. Waters and her team collected nasal cells from 24 children, aged 5 to 17 years, to create lung organoids. Each organoid was subjected to all four existing CFTR treatments, and the researchers compared the lab results with real-world patient outcomes, including lung function and overall medication response.
The findings were promising, demonstrating a strong correlation between organoid responses and clinical outcomes. A/Prof. Waters noted, “While patients are routinely transitioned between modulators, this is the first paediatric study to compare all clinically available CFTR modulators head-to-head in airway organoids—and relate those results to real-world clinical responses.”
In parallel, the team conducted whole-genome sequencing on each child’s DNA, hoping to uncover patterns that could further predict drug responses. Unfortunately, this aspect of the research did not yield the anticipated results.
The ongoing work at UNSW Sydney represents a significant advancement in the fight against cystic fibrosis, with the potential to enhance treatment precision and improve the quality of life for affected children. As research continues to evolve, there is hope that personalized medicine will offer new avenues for managing this complex and challenging condition.
