Periodic Reporting for period 4 - C9ND (C9orf72-mediated neurodegeneration: mechanisms and therapeutics)
Reporting period: 2020-04-01 to 2021-03-31
Frontotemporal dementia and amyotrophic lateral sclerosis are devastating neurodegenerative diseases which have no effective therapies. Frontotemporal dementia can cause changes in a person’s personality, behaviour or language abilities. Amyotrophic lateral sclerosis causes muscle weakness, which rapidly leads to paralysis and death. Some people can develop both frontotemporal dementia and amyotrophic lateral sclerosis, which indicates that the two diseases can be caused by the same factors. The most common cause of both diseases is a mutation in the C9orf72 gene. The mutation comprises of a small section of DNA within the C9orf72 gene that becomes repeated hundreds to thousands of times. This type of mutation is termed a repeat expansion. We have previously shown that these repeats are very harmful to neurons. This project aims to better understand how the C9orf72 repeats causes neurons to die and to identify new genes that can protect against their harmful effects. Our final objective was to investigate new compounds that can target the C9orf72 repeats and assess their potential as therapeutics. We successfully completed these objectives. We also identified new compounds that reduce harmful products of the C9orf72 repeat expansion. Our exciting new data also identified genes that can reduce the harmful effect of the C9orf72 repeat expansion. These genes will be tested for their ability to act as gene therapies in the future.
We previously engineered fruit flies to contain the C9orf72 repeat expansion. These flies have a shortened lifespan. We have now analysed over 2000 genes to assess which ones can protect against the harmful effects of the C9orf72 repeat expansion. We have identified 16 genes that extend the lifespan of the C9orf72 repeat-containing flies. This is a major achievement and provides significant new insight into the causes and potential therapeutic avenues for C9orf72 frontotemporal dementia and amyotrophic lateral sclerosis. We have also analysed the effects of the C9orf72 repeat expansion in human neurons and identified specific pathways within the cell that are affected. We found ways to enhance these defective pathways and showed they reduce the harmful effects of the C9orf72 repeat expansion. In addition, we have also identified new compounds that can bind to the C9orf72 repeats. We have shown that these compounds reduce the toxic properties of the repeats in both fruit flies and neurons derived from people with the C9orf72 repeat expansion. This provides proof of concept for further development of drugs using this approach.Many of these findings have been published in scientific journals and presented at scientific conferences. 22 papers have been published in total that related to our work and some have been very highly cited, showing that they have influenced other researchers.
We have identified 16 genes that can alleviate the harmful effects of the C9orf72 repeat expansion in fruit flies. None of these genes have been implicated previously in C9orf72 disease. Therefore this marks a very clear progression beyond the current state of the art. Some of these genes are candidates for use as gene therapies and this will be tested in the future.