SickKids researchers gain important insight on “undruggable” disease

Novel research from The Hospital for Sick Children (SickKids) may lead to new drug therapies for children with cerebral cavernous malformation (CCM) – a disease that is caused by the progressive growth of large lesions in the blood vessels in the brain and spinal cord. The findings are published in Nature Communications. 

The main problem for patients with CCM is that there are currently no drugs available to manage or suppress the growth of these lesions in the brain, so the only way to remove them is invasive neurosurgery.

CCM affects about one in 500 people and can arise sporadically or can be inherited through a mutation in one of three genes; CCM1, CCM2 or CCM3. Some individuals with cerebral cavernous malformations never experience any symptoms, while others experience headaches, seizures, paralysis, hearing or vision loss, and bleeding in the brain (cerebral hemorrhage). 

Although mutations in all three of these genes lead to the same problems in the blood vessels, the loss of the CCM3 gene leads to early onset of the disease, often presenting in children, and has the most severe prognosis for patients.

A research team led by Dr. Brent Derry, Senior Scientist in Developmental & Stem Cell Biology at SickKids and Associate Professor in the Department of Molecular Genetics at the University of Toronto, wanted to know what distinguished the biological function of CCM3 from CCM1 and CCM2. In collaboration with Dr. Anne-Claude Gingras at the Lunenfeld-Tannenbaum they combined the power of genetics and proteomics (the large-scale study of proteins) to determine how the CCM3 gene functions in the context of a living organism.

Using a worm as their disease model (C. elegans), the team discovered a novel mechanism by which CCM3 functions in vivo. They learned that CCM3 is essential for growth and maintenance of the tube structure of the blood vessel, and when CCM3 is mutated, this interferes with a process called endocytic recycling. Thus, in CCM3 mutants the healthy development of this biological tube is compromised and cysts form that resemble cavernous malformations found in the vasculature of human patients.  

Building from this research, Derry and Dr. Peter Roy at the Donnelly Centre (University of Toronto) were recently awarded an E-RARE grant to screen for small compounds to correct defects in CCM mutants. Together with international collaborators in Germany and France they are using worms, zebrafish and mouse models of CCM disease to identify potential drugs for treating this disease.

This work was supported by a CIHR grant to Drs. Gingras and Derry. Dr. Benjamin Lant was supported by a CIHR-funded Excellence in Radiation Research for the 21^st Century (EIRR21) training grant.