Press Release

Monday, 10 September 2018

REBIRTH researchers identify potential drug to treat rare condition

A substance has been identified that alleviates symptoms of a rare vascular disease called cerebral cavernous malformation (CCM). It was found thanks to comprehensive analysis – using a mouse model – within a consortium headed by a researcher at Hannover Medical School (MHH) and the University of Potsdam. In CCM sufferers, malformations of cerebral blood vessels may lead to brain haemorrhage and strokes. The scientists screened pharmaceuticals already approved for use in humans. Other members of the consortium include the Hospital for Sick Children (SickKids) in Toronto, Canada, the Université Paris Diderot and INSERM at Grenoble, France, as well as the Berlin-based Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). “At present, the only treatment option for this condition is a neurosurgical procedure, although this is possible only if the malformations are not too deep inside the brain and not in parts of the brain essential for survival,” explains Professor Salim Seyfried of MHH’s Institute of Molecular Biology. He is coordinating the study, which is being conducted by a transnational consortium (part of the E-RARE network) called CCMCURE. “There is an acute need for a medicine to treat this disease. In such a case, screenings of this kind – in which already existing drugs are analysed for potentially new uses – are the quickest way of finding one.” The international team published its findings in the periodical EMBO Molecular Medicine.

The EU-funded consortium tested more than 5,000 compounds approved by the US Federal Food and Drug Administration (FDA) using established model systems for CCM, including nematodes, zebrafish eggs and (in humans) vascular wall cells. “The pharmaceuticals identified have allowed us to discover the relevant molecular signalling pathways and networks that may play a part in this condition. Analysing the molecular networks involved in CCM will also help in the development of combinatorial approaches to tackling this disease,” says MHH professor Seyfried, who also heads a research unit at the University of Potsdam. Additionally, some of the compounds identified in the analysis are candidates for treating other conditions of molecular origin.

Indirubin-3’-monoxime identified as a potential drug

Drawing on the outcome of analyses using animal models and human cells, the scientists began by investigating the effect of indirubin-3’-monoxime in mice. Indirubin-3’-monoxime is a pharmaceutical with only mild side-effects that is used in traditional Chinese medicine, where it is frequently chosen to treat leukaemia and other chronic diseases. In molecular and functional studies, the researchers had already discovered that indirubin-3’-monoxime prevents these malformations in human vascular cells and in zebrafish eggs. Their investigations using a mouse model revealed that ‘feeding’ juveniles with indirubin-3’-monoxime reduced the impact of the malformations.

Cerebral cavernous malfunction (CCM)

CCM is a relatively frequent condition that may occur in 0.5% of the population. The disease is generally not hereditary. However, these malformations in the brain may (in some cases) occur due to inherited mutations of three genes CCM1, CCM2 or CCM3). This familial form of the condition is very rare, with only one individual in 3,000 affected. The scientists believe early onset and severe progression of the disease are, in particular, associated with the mutation in the CCM3 gene.

Alongside the EU (the study’s chief funder), the REBIRTH Cluster of Excellence also financially assisted the project.

The image, created by graphic designer Kat Menschik, shows a cerebral cavernous malformation (berry) in a dense carpet of medicinal-herb flowers. Some of the active ingredients identified are obtained from these plants. The zebrafish in the picture represent the animal models used.

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