Cerebral Diseases
Developing a therapeutic drug to treat Cerebral cavernous malformation
Dr Xiangjian Zheng
Centenerary Institute of Cancer Medicine and Cell Biology, Sydney
Funded By Ledonne Family in memory of Stephanie
Co-Investigators : Dr Jaesung Choi

Project Summary:

Cerebral carnevous malformation (CCM), also known as Angioma or Cavernoma, is a cerebrovascular disease which affects the blood vessels supplying the brain and is the leading cause of strokes in young patients. The disease causes collections of abnormal vessels to form throughout the brain, in variable size and quantities. Currently, surgery is the only treatment option and requires the CCM lesion to be in a respectable part of the brain. Due to CCM lesions presenting in variable size, number and locations in the brain, surgical removal is often not feasible. With no therapeutic drug treatment available, many CCM patients are left at risk of life threatening conditions such as brain hemorrhages, stroke and neurological deficits. We dedicate our research effort to addressing this problem, focused on providing a non-invasive, therapeutic approach to CCM treatment to improve the outlook and well-being of CCM patients.

Genetic studies have identified the cause of CCM disease as ‘loss-of-function’ defects in CCM1, CCM2 and CCM3 genes. We have used this as a basis for our research and have developed novel research techniques and established specialised mouse models to explore the molecular pathogenesis of CCM disease. By deleting the CCM1, CCM2, CCM3 genes in endothelial cells (cells lining inner side of blood vessels), our unique mouse models mimic the manifestation of the disease in humans. Using these models, we uncovered causal relationships between CCM genes and several proteins (MEKK3, Klfs and Adamts) which are essential for CCM lesion formation. Genetically decreasing MEKK3 and Klf in the models prevented these mice from forming CCM lesions. We anticipate targeting a third protein Adamts will effectively treat CCM disease. Drugs to target this protein have been developed in research phase by pharmaceutical companies for a different disease. This project will build upon these discoveries, aiming to provide the basis for drug development, identify potential drug candidates and reduce the disease burden for CCM patients.