Press Releases

Entry from: 26.11.2018
Category: Press Releases, News

Researchers identify potential active drug substance for rare disease

Cavernous malformations in the brain: Indirubin-3-monoxime may be able to relieve symptoms
In a wide-ranging study involving zebrafish, a consortium of the Hannover Medical School (MHH) and the University of Potsdam (UP) led by Professor Salim Seyfried has identified a substance that alleviates the symptoms of the rare blood vessel disease of cerebral cavernous malformations (CCM). The consortium also includes the Hospital for Sick Children (SickKids) in Toronto, Canada, the Université Paris Diderot and the INSERM Grenoble in France, as well as the Leibniz –Forschungsinstitut für Molekulare Pharmakologie(FMP) in Berlin, Germany.

The picture symbolizes a malformation of blood vessels (“berry”) surrounded by medicinal plants and zebrafish. Some of the active substances identified are extracted from the medicinal plants. The zebrafish shown symbolize one of the animal models employed. Graphic designer Kat Menschik

Patients suffering from the disease have accretions of the blood vessels in the brain, which may lead to brain hemorrhages and strokes, even in teenagers. The researchers had already examined active substances approved for combating other human diseases.
“Currently, the disease can only be treated by a neurosurgical procedure, though only if the adhesions are not too deep inside the brain or in vital brain regions,” explains Professor Salim Seyfried. He coordinates the study carried out by the transnational E-RARE-Net CCMCURE consortium.
“A drug for the treatment of the disease would be urgently desirable. Such studies of existing drugs for potential new indication areas are the fastest way to find medications.” The international team published its findings in the “EMBO Molecular Medicine” journal.

Search for active substances in the screening unit
The FMP’s screening unit FMP, led by Dr. Jens Peter von Kries, has established a number of tests with cell culture systems and the nematode C. elegans in order to analyze the consequences of the mutation on the development of blood vessels, one example of which is the high-speed imaging in 2D of heart contractions through volumetric changes or through blood vessel formation by HUVEC cells.
The decision to start off with a library of around 3,300 active substances approved by the Federal Food and Drug Administration (FDA) already led to one positive result after screening around 600 active substances. These hits can now be tested on patients, e.g. at the Hospital for Sick Kids in Toronto (Canada, patient cohorts available). The hits have been validated for positive effects in mice and human cell culture systems similar to the clinical picture. The mutation studied is rare and the number of such patients small, but other mutations that have the same effect on blood vessel formation could dramatically increase the number of potential beneficiaries of this new treatment option. .
The consortium, supported by the European Union, tested more than 5,000 FDA-approved compounds on established disease model systems for cerebral cavernous malformations, including nematodes, zebrafish, and the cells of human blood vessel walls. “The active substances identified have allowed us to explain the relevant molecular signaling pathways and networks that could play a role in the disease. The analysis of the molecular networks relevant for cerebral cavernous malformations will also help develop combinatorial approaches to combating this disease,” Professor Seyfried said. Moreover, some of the compounds identified during the analysis are candidates for the treatment of other molecularly related blood vessel diseases. 

Indirubin-3 monoxime identified as a potential remedy

Based on the results of the analyses involving the animal models and human cells, the scientists first investigated the effect of indirubin-3 monoximes in the mouse model. Indirubin-3-monoxime is a drug that causes only minor side effects. Its origin is in traditional Chinese medicine, where it is frequently used to treat leukemia and other chronic diseases. The researchers had already discovered in molecular and functional studies that indirubin-3-monoxime inhibits adhesions in human blood vessel cells and zebrafish eggs. When examining mouse models with stroke-like bleeding in the brain, they discovered that feeding young mice with indirubin-3 monoxime alleviated the burden from adhesions.
Cerebral cavernous malformations (CCMs)
Cerebral cavernous malformations are relatively common diseases that may occur in 0.5 percent of the population. As a rule, the disease is not hereditary. The malformations in the brain may also occur due to familial inherited mutations in three genes: CCM1, CCM2 or CCM3. This familial form of the disease is very rare; only one in 3,000 people is affected. Scientists associate the mutation in the CCM3 gene specifically with an early onset and severe progression of the disease.
In addition to the main sponsor of the study, the European Union, the REBIRTH Excellence Cluster also helped to fund the project.

Source: Cécile Otten, Jessica Knox, Gwénola Boulday, Mathias Eymery, Marta Haniszewski, Martin Neuenschwander, Silke Radetzki, Ingo Vogt, Kristina Hähn, Coralie De Luca, Cécile Cardoso, Sabri Hamad, Carla Igual Gil, Peter Roy, Corinne Albiges‐Rizo, Eva Faurobert, Jens P von Kries, Mónica Campillos, Elisabeth Tournier‐Lasserve, W Brent Derry, Salim Abdelilah‐Seyfried. Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations. EMBO Molecular Medicine (2018) 10, e9155. DOI: 10.15252/emmm.201809155

Press release: MHH/Rebirth

Further information on the biological basis of the disease can be obtained from:

Professor Salim Seyfried
MHH-Institut für Molekularbiologie
Telephone (+49) 511 532 5933 or (+49) 331 977 5540

If you have any questions about active substance searches, please contact
Dr. Jens Peter von Kries
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Head of the Screening Unit
Tel.: +49(0)30 9406 2982

Silke Oßwald
Public Relations
Tel.: +49(0)30 94793 104

The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB, Research Association Berlin). The FVB unites eight science, life science and environmental science institutes in Berlin. More than 1,900 staff work in these institutes. The award-winning institutes are members of the Leibniz Association. The Forschungsverbund Berlin e.V. (FVB) emerged from the former DDR Akademie der Wissenschaften (Academy of Sciences in the former German Democratic Republic) in 1992.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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