In Search of a Better Treatment for Cystic Fibrosis

Cystic Fibrosis or CF is a genetic disease that can be caused by many different mutations in the DNA. Therefore, when someone is diagnosed with cystic fibrosis, many questions remain unanswered about the course of treatment. For part of the people with CF, medication is available, and for the remaining part, screening with organoids offers perspective. Lisa Rodenburg received her doctorate on February 8th for her research into improved forms of this screening.   

What causes cystic fibrosis?

Cystic fibrosis or CF is a genetic disorder: a mutation in the DNA causes a pump in the cell membrane to malfunction. This pump is responsible for the transport of salts and thus, through osmosis, water across the membrane, ensuring a balance in and around the cells. In CF patients, the malfunctioning pump causes a disruption in the water balance, resulting in less water in the mucus membranes, in turn causing the mucus to be tough.    

Many mutations, some with treatment  

The challenging aspect about CF is that it can be caused by some 2,000 different mutations, and thus treatment is not straightforward. For several years, about eighty percent of people with CF have been eligible for the drug Kaftrio. The remaining twenty percent rely on a screening that can indicate whether the drug might also work for them.  

A screening with organoids from the patient

The screening, developed at the Regenerative Medicine Center Utrecht, is the first clinical application of organoids – small pieces of tissue that can be grown from harvested cells and resemble the tissue they come from. Currently, an intestinal biopsy is required from someone with CF to produce the intestinal organoids required for the assay. These organoids have the useful property of swelling during the assay when the pump in the cells works properly.  

In people with CF, this pump does not work, so the organoids do not swell unless there is an effective medication. The organoids can be tested in large quantities at the same time, and the swelling combined with fluorescence allows for automated microscope assessment of whether the tested drugs are effective. The screening can ensure that more people with CF have access to an effective treatment. 

In search of better screening

The first part of Lisa Rodenburg's research, in the team of Jeffrey Beekman, Kors van der Ent and Gimano Amatngalim, focused on using other types of organoids for screening, namely from the airway. In comparison to intestinal organoids, airway organoids are less stressful to obtain for the patient because there is no need to take an intestinal biopsy, as the cells are taken from the nose – with a swab just like in a Covid test. Rodenburg managed to use these organoids for screening, but it turned out to be trickier than expected.    

More pumps, more possibilities

Lisa and her group saw that airway organoids contain more pumps than the pump affected in CF, making the effect of the defective pump harder to see. ‘It got us thinking, and eventually we saw it as an opportunity. What if we could stimulate these other pumps and thus alleviate the symptoms of CF through a different route?’ 

Therefore, in the second part of her research, Rodenburg looked at drugs that might act on these alternative pumps. ‘From this screening, a number of candidate drugs emerged that could potentially be effective. Now it's a matter of finding out exactly how they work. Rodenburg hopes that airway organoids can be used in the future to help people with CF find the best treatment. 

A great time in the RMCU

After a great time at the Regenerative Medicine Center Utrecht, Rodenburg now works as a physician at the WKZ, in the department of clinical genetics. Looking back on her doctoral research, one anecdote came to mind. 'I was home for Christmas, telling my brother about the challenges of my research,' Rodenburg begins. 'We wanted to scale up drug screening from 96 well plates to 384 well plates to generate more capacity. My brother, a data scientist, had some ideas about using artificial intelligence to recognize organoids in the microscopic images. Eventually he helped program my analysis and became a co-author in one of my scientific publications.' 

This article was written by Francesca Pileri.