In search of rare door-openers for young patients with cystic fibrosis

As a Clinician Scientist, Dr. Simon Gräber divides his time between patient care at the clinic and research in the lab. The future consultant in pediatric and adolescent medicine specialises in cystic fibrosis, also called “mucoviscidosis”, a rare hereditary metabolic disease which often already appears in childhood. The disease used to entail a short life expectancy. Meanwhile, there are some very good therapy options, though not for all patients equally. We talked with the Clinician Scientist, whose project is being funded by the Charité Foundation, about his research, his patients and, not least, about what motivates him at a personal level.

Dr. Gräber, in your research project you’re focused on the pharmacological modulation of rare CFTR mutations. What exactly does that mean?

The cause of cystic fibrosis lies in the mutations of a gene called the “CFTR” gene, which is short for “cystic fibrosis transmembrane conductance regulator”. There are about 2,000 different mutations of this gene. Some of them occur far more frequently than others. 90 percent of patients have common mutations. For these cases, medications have been developed that are an excellent help nowadays. However, 10 percent of patients have rare mutations. There are currently still no medications for this group, i.e. the rare cases. We’d like to help them with our research.

How exactly do you plan to help this smaller group of cystic fibrosis sufferers?

We’re developing a medication for this patient group that repairs a defective chloride channel which typically occurs in cystic fibrosis. Basically, you can imagine it as a door. The door has to be open for the mucus to be able to dissolve. However, in the case of these patients, the door is broken. It’s locked or jammed closed. The medication has to unlock and open the door, and keep it open. As there’s still no gene therapy for this, we’re working pharmacologically, i.e. with medications.

Cystic fibrosis is above all known as a disease that already appears in childhood. Who are your patients?

We do in fact treat a lot of children. In the past, families often had to embark on a long Odyssey through the health system until they got the right diagnosis for their sick child. So back then, the diagnosis was often a psychological relief for those concerned. Since 2016, we have comprehensive screening of all newborns in Germany. This is excellent, as it means you can detect cases earlier and start with treatments sooner. However, psychologically, it’s often more difficult for the families. They thought their child was healthy and suddenly they find out it has a rare hereditary disease. Here, it’s extremely important to communicate and provide information in a sensitive way. Medicine has made great advances over the past few years. In the past, children with this disease didn’t reach adulthood. Today, we have an average life expectancy of around 50. In addition, cystic fibrosis can also be caused by rare mutations which don’t make themselves felt until the age of 30, 40 or 50. So we take care of adult patients too.

What led you to begin researching this disease?

I already had an enthusiasm for pediatric and adolescent medicine during my studies. As chance would have it, it was sport that led me to cystic fibrosis research. I played lacrosse and there were a few colleagues on my team who were working in Professor Mall’s laboratory.