Targeting bile-duct enzymes in primary sclerosing cholangitis

Bile is essential for digesting dietary fats. It is produced in the liver and reaches the intestine via the gallbladder and the bile ducts. When these ducts become chronically inflamed, people may experience agonizing itching, fatigue and weight loss, and the disease can progress to liver failure. Primary sclerosing cholangitis (PSC) often leads to the need for a liver transplant. According to MHH, PSC typically develops between ages 30 and 50, and around one in 10,000 people in Germany are affected.

At present, PSC cannot be cured; clinical care focuses on symptom relief. Antibiotics may be used, but broad-spectrum treatment can contribute to antimicrobial resistance. Against this background, MHH and HZI are pursuing a targeted approach in the StopPSC project, based on compounds from flu medication.

"We are developing tailor-made therapies for primary sclerosing cholangitis using optimised active ingredients to improve the prognosis for patients," says the project spokesperson, Prof. Benjamin Heidrich from the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at MHH.

The state of Lower Saxony and the Volkswagen Foundation are supporting "Sialidase targeting pathoblocker therapy for primary sclerosing cholangitis" (StopPSC) with two million euros under the "zukunft.niedersachsen" programme. The funding scheme supports projects that aim to develop new diagnostics and therapies for rare diseases, defined as conditions affecting fewer than five in 10,000 people, and which are often difficult to diagnose and treat.

The project is based on observations that the bile ducts host a complex community of bacteria even in healthy individuals. When certain species become more prevalent, PSC may worsen. The key issue is not the bacteria themselves but enzymes they produce. Sialidases can damage bile-duct cells, reducing protection against bile acids and promoting inflammation.

StopPSC aims to develop a compound that can specifically inhibit sialidases. Such substances are described as pathoblockers, because they block disease-driving factors produced by bacteria rather than broadly targeting the entire microbiome.

• computer-based screening and laboratory testing of candidate compounds from flu drugs
• investigating how active ingredients reach the bile ducts and distribute there effectively
• developing a patentable approach that companies could later translate into clinical application

StopPSC builds on prior work from the RESIST Cluster of Excellence and the German Centre for Infection Research (DZIF), which is also providing financial support.

MEDICA-tradefair.com; Source: Hannover Medical School