From laboratory research to treatment for cystic fibrosis
Cystic fibrosis (CF) is a hereditary disease characterized by the accumulation and toughening of mucus in various organs, leading to inflammation and reduced organ function. While many people with CF have access to existing therapies, 10% of patients have a specific mutation that is difficult to treat.
Sacha Spelier investigated various treatment strategies for these patients, focusing on combining several drugs with different working mechanisms. On June 20, she successfully defended her dissertation on this and obtained her PhD.
What goes wrong in cystic fibrosis?
The mucus of patients with CF becomes tough due to a mutation in the gene encoding the CFTR protein, Sacha explains: ‘A defect in the CFTR gene causes non-functioning CFTR protein. This protein is an ion channel which regulates the moisture content of mucus and is found in organs that produce mucus, such as the lungs and intestines.’ Tough mucus in the lungs causes shortness of breath and increases the risk of infections.
‘Most patients have a mutation that disrupts the function of the CFTR protein. They can often be treated with medication that improves the protein's function,’ Sacha continues. ‘However, there is also a group of patients with so-called nonsense mutations that prevents the CFTR protein from being produced at all, and there is currently no treatment available for these patients.’
In search of an effective drug
In her dissertation, Sacha focused on finding a treatment for CF patients with this specific mutation. In the first part of her research, she primarily looked at drugs that “ignore” this DNA defect, allowing CFTR protein to be produced. Although this group of medications restored CFTR protein function in combination with other drugs, they did not continue with this strategy, Sacha explains. 'The drugs we tested have not yet been approved in clinical trials, and before they will be tested in a clinical trial setting, more preclinical studies are warranted. Therefore, we started looking for something that could be brought to the clinic more easily.'
Assessing CFTR function in patient tissue
Testing drugs in patient tissue is important for their clinical translation. Sacha, part of Jeffrey Beekman’s research group, elaborates on their approach: 'We use a swelling test with intestinal organoids, which are 3D balloon-like structures derived from patients’ tissue. Healthy organoids with functioning CFTR protein absorb water and swell. If the protein doesn't work, as in CF organoids, the balloons collapse. We can also administer medication to these organoids. If the balloons swell, we know the medication works.’
Combination therapy for effective CF treatment
Since the previously tested drugs could not be used directly in the clinic, the second part of Sacha's research focused on finding a treatment that could be readily accessible to CF patients. ‘To achieve this, we explored drugs that are already FDA-approved for the treatment of other diseases,’ she explains. ‘We evaluated 1400 approved drugs using the swelling assay, and three families of drugs turned out to be suitable for treating cystic fibrosis.’
Sacha proudly shares the outcome of this final study: ‘We concluded with a clinical trial study in a CF patient. The swelling test showed that the combination of drugs caused swelling of the patient's organoids, indicating restored CFTR function. In the trial, the patient was given the same treatment, with positive results. His lung function and quality of life improved significantly.’
Sacha's highlights
'The transition from drug research in the laboratory to actually discovering a treatment for a CF patient is very special,’ Sacha states. She expresses that she enjoyed her PhD journey, particularly due to the research group in which she worked. Alongside the team effort in her major projects, Sacha also bonded with her colleagues in different ways.
Together with her co-workers, Sacha trained twice for the Skate4Air event, a long-distance ice-skating event on natural ice which took place in Sweden in 2024. ‘We skated 200km in one day, raising money for cystic fibrosis research.’ A great experience, says Sacha: ‘I found it very valuable to be part of this tight community and to engage with patients and individuals personally affected by the disease. This experience stands out as one of the biggest highlights of my PhD.’
Looking ahead, Sacha can still be found at the RMCU, where she will continue as a PostDoc in Jeffrey Beekman’s group. ‘There are still some loose ends from my PhD research that I will continue working on, but there will also be room for new projects,’ she says.
This article was written by Karen van der Doelen.