Prof. Dr. Thorsten Marquardt im Labor

„From ultra rare to rare“: very rare disease points the way for cystic fibrosis therapy

Eva Luise Köhler honors scientists from Münster and Regensburg

Berlin, February 2021. Prof. Dr. Thorsten Marquardt and Dr. Julien Park from Münster University Hospital and Prof. Dr. Karl Kunzelmann from the University of Regensburg have been awarded the Eva Luise Köhler Research Prize for Rare Diseases 2021 for a promising repurposing approach for the treatment of cystic fibrosis. With the awarded money of 50,000 euros, the researchers will investigate the extent to which an active ingredient previously approved for the treatment of tapeworms is also suitable for the regulation of derailed mucus production in mucosviscidosis. To this end, the scientists intend to develop an inhalation solution based on Niclosamid®. This active ingredient, which has been well researched for decades and has been repeatedly discussed for cancer treatment for the past 10 years, also has antiviral and antibacterial properties, which has recently made it an interesting candidate for the treatment of COVID-19.

Cystic fibrosis (CF) is a congenital metabolic disease caused by mutations in the gene CFTR. This encodes a chloride channel called the "Cystic Fibrosis Transmembrane Conductance Regulator", which keeps the salt-water balance in various organs in the body in balance. If the chloride channel does not function properly, a viscous mucus is formed that gradually clogs vital organs, first and foremost the lungs.

With around 8,000 people affected in Germany alone, cystic fibrosis is one of the most common serious rare diseases. There are now treatment approaches for some mutations, but therapies targeting the basic defect are not available for all patients. Life expectancy in cystic fibrosis is still generally very short.

A newly discovered very rare disease leads to a new treatment perspective for a whole other rare disease

The therapeutic approach developed in Münster is based primarily on the assumption that blocking another chloride channel (TMEM16A) could lead to a reduction in mucus production in cystic fibrosis patients. In developing this working hypothesis, coincidence came to the aid of the Münster physicians, as it often does, as Thorsten Marquardt explains: "Parents presented a few-month-old girl with failure to thrive and abdominal problems, who unfortunately subsequently died. We discovered a previously unknown new disease in her and her older brother, which led to a loss of TMEM16A function. The surprise: the loss of TMEM16A also led to a loss of CFTR function - but without any symptoms of cystic fibrosis appearing at that time. This, of course, made our ears prick up - after all, this was not the first time we experienced that a new diagnosis of one rare disease helps to better understand another."

Now, the protective effect of TMEM16A inhibition is to be tested by administering the active ingredient niclosamide, which has been used successfully for many decades to treat worm infections and effectively blocks this channel.  As part of an interdisciplinary collaboration between human physicians, physiologists and pharmacists, an inhaled niclosamide molecule will first be developed and then tested in a mouse model. If the efficacy and safety of the therapy concept are confirmed, it could benefit many patients in the future. This would be a great opportunity, especially for those patients who do not benefit from CFTR modulators.

Doctors and scientists work hand in hand

Prof. Dr. Annette Grüters-Kieslich, Chairman of the Foundation, explains why the translational research project was able to convince not only with its pragmatic repurposing approach, but also with its special closeness to patients: "With Professor Thorsten Marquardt and his young colleague Dr. Julien Park, we are witnessing two generations of physicians who embody the forward-looking model of the clinician scientist in an almost ideal way. In their collaboration with basic researchers, they prove that successful research and care in the field of rare diseases are inseparable and should know no institutional boundaries."

The Eva Luise Köhler Research Award for Rare Diseases will be awarded for the 14th time in collaboration with the Alliance of Chronic Rare Diseases (ACHSE) e. V.. Due to the pandemic, the award ceremony will take place for the first time not at the end of February, in the context of the Rare Disease Day, but on June 17, 2021 at the Berlin Brandenburg Academy of Sciences.

Pictures: UK Münster
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