The SMND RAG are thankful to Dr Alexander McGown who presented ‘Fishing for cures: Zebrafish for MND drug discovery’ at the last quarterly meeting. Dr McGowan is working as part of the Ramesh Lab group at SITraN and their lab is focused on using zebrafish to identify novel therapeutics for the treatment of MND.
Zebrafish are a fantastic organism for researching neurodegenerative diseases as they are genetically and structurally very similar to humans, meaning we can investigate human diseases in the fish. Zebrafish lay hundreds of embryos which develop rapidly, including a functioning nervous system within 48 hours of development, meaning they are excellent models for doing large scale drug screens, something that would not be possible in common laboratory models, such as mice and rats. We have developed multiple zebrafish models of MND for drug discovery, including for many of the major genetic causes of ALS, including SOD1, C9orf72 and TDP-43.
Using the state of the art drug screening facilities at SITraN we have developed a drug screen that can be completed in 4 days and can screen over 400 drugs per week. Using the high content imaging and drug delivery systems we have optimised a screen for drugs that reduce toxicity in the central nervous system. Our initial screen investigated over 2000 drugs and identified a novel class of ion channel modulators that can reduce neuronal toxicity in mutant SOD1 zebrafish. We have now taken this forward and screened a further 5000 drugs to identify novel disease mechanisms and drug targets. The top hits our now being validated in behavioural testing and in other models to confirm the effects.
We believe there is a space in the drug discovery pipeline where zebrafish can play a key role in finding new treatments. Cell models are fantastic for drug screening but lack the complexity of a whole living organism, whereas classical animal models, like mice, have the complexity, but are slow and cumbersome for drug discovery. We believe that zebrafish can provide a bridge between the two models leading to better therapies being tested and novel drugs being discovered to treat MND.