Validation of Repulsive Guidance Molecule A (RGMa) as a Neuroprotective Treatment in Parkinson’s Disease
University Health Network, Toronto Western Research Institute, University of Toronto
In 2002, we discovered a protein in neurons that could repel the growth of neurons and was important in the development of the nervous system, we called it Repulsive Guidance Molecule A (RGMa). In the last decade, and more, we have discovered how RGMa exerts its actions, via a receptor called neogenin, and found that RGMa plays a role in injury to the brain in several disorders, including stroke, glaucoma and spinal cord injury and blocking one specific interaction between RGMa and neogenin has therapeutic potential in these disorders. To date, the potential role of RGMa in Parkinson’s disease has been overlooked, this project provides a program of research to redress this balance. We will firstly synthesise specific antibodies to disrupt the interactions between RGMa and neogenin. We will then define how we can cause such disruption in the brains of rats. We will then assess the ability of disrupting RGMa-neogenin interactions to reduce symptoms and neurodegeneration in rats modelling the pathology of Parkinson’s disease.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
The project will validate whether interfering with RGMa-neogenin interactions is a viable therapeutic strategy in Parkinson’s disease. We do not necessarily suggest that the antibodies we produce to disrupt the interactions could become a therapy in themselves, though this is possible. The principle goal of the work is, rather, that by validating the potential of a novel therapeutic target, we will drive and enable the development of small molecule drugs that can be administered orally.
We anticipate that disrupting RGMa-neogenin interactions will reduce parkinsonian symptoms and loss of dopamine neurons in rodents modeling the pathology of Parkinson’s disease. If this hypothesis is supported, the work will encourage a new area of Parkinson’s research, to develop a therapy based upon targeting this mechanism.
We successfully synthesised antibodies to disrupt the interactions between RGMa and neogenin. We then moved on to define how to use them to disrupt the RGMa and neogenin in the brains of rats. Our intention was to investigate the effects of such disruption in rats showing the pathology of Parkinson’s disease (PD). In some experiments we found evidence that our antibodies worked effectively but in others they did not. Thus, we were not able to reliably draw any conclusions on the effect of the RGMa in our animal models and we terminated the project. We remain interested in the therapeutic potential of interfering with RGMa-neogenin signaling in PD and, if more reliable means of engaging this target are developed, e.g. small molecule drugs, were available, we would re-visit this approach.