Using a zebrafish model to understand the early spread of MND and to screen potential new drugs
This project will involve the use of a zebrafish model of MND to efficiently screen over 2,000 potential drugs for any beneficial effects. The zebrafish will also provide the researchers with opportunities to study and better understand how neuronal stress develops and spreads in MND, offering insight into the earliest stages of the disease.
- Dr Tennore Ramesh, Prof Pam Shaw
- Sheffield Institute for Translational Neuroscience, University of Sheffield
- £195,000 (Biomedical project)
- 36 months, starting October 2011
Despite the wide availability of mouse models of MND, they are not suitable for undertaking large drug screens due to costs, space and time required. Zebrafish, like mice and humans, are vertebrates and many genes are similar in human and fish. Dr Ramesh and colleagues have developed a zebrafish model of MND that incorporates a mutated form of the SOD1 gene. The researchers have already established that this model shows most aspects of MND seen in mice and humans, including muscle wastage, paralysis and premature death.
When Dr Ramesh’s team treated the mutant fish embryos with riluzole, a drug that is already used to treat MND, they saw a reduction in neuronal damage. This confirms that their fish model can be used to quickly demonstrate the effects of potential drugs and will allow them to use it for a relatively efficient large scale screening programme of 2000 drug compounds. Many of the compounds they will screen are already approved for human medicinal use and if any of these show promise, translation into human clinical trials could be developed in a relatively rapid time scale.
Dr Ramesh and colleagues have also shown that some neurones in their model display ‘stress’ even when the fish are developing as embryos, suggesting that the neurones in MND are constantly in a state of stress that predisposes them to greater damage and eventual death. Using the fish model to improve understanding of how neuronal stress develops and spreads may contribute to eventual identification of markers of the earliest stages of the disease, which are important for effective drug development.
A recent paper published from this study in December 2012 showed that ‘interneurons’ are the key in early stages of MND. Read about this on our research blog.