UCL School of Pharmacy


Compounds identified by UCL team to target degenerative diseases

12 December 2017


Professor Stephen Neidle (Emeritus Professor, UCL School of Pharmacy) and Dr Gary Parkinson at the School have been involved in an important study on the diseases myotrophic lateral sclerosis and frontotemporal dementia, in collaboration with the team led by Professor Adrian Isaacs (UCL Institute of Neurology) and a group at Georgia State University, Atlanta USA, led by Professors David Boykin and David Wilson.

The study has been published in the November 7th issue of the journal EMBO Molecular Medicine, and has been highlighted in a News and Views article in the November 24th issue as well as in the Alzforum news website.

These are devastating degenerative diseases with no treatments currently available. A mutation in the C9orf72 gene is the most common cause of both amyotrophic lateral sclerosis and frontotemporal dementia, accounting for approximately 10% of all cases. This C9orf72 mutation, termed a repeat expansion can form a distinct secondary structure termed a G-quadruplex. This then leads to the formation of dipeptide repeat proteins, which are extremely neurotoxic. Therefore, reducing the levels of these dipeptide repeat proteins is a potential therapeutic strategy.

Active neurons

The team were able to identify three compounds that specifically target the C9orf72 RNA G-quadruplex. They identified three compounds with similar chemical structures that were able to selectively bind the C9orf72 repeat G-quadruplex. C9orf72 patient-induced pluripotent stem cell (iPSC)-derived neurons, and fruit flies harbouring the C9orf72 repeat expansion, were treated with these compounds. It was found that the compounds reduced the levels of the damaging dipeptide repeat proteins in both the iPSC-neurons and the fruit flies. Furthermore, they improved the survival of the C9orf72 repeat fruit flies.

These results provide the first proof of principle that targeting the C9orf72 repeat G-quadruplex is a potential treatment strategy for amyotrophic lateral sclerosis and frontotemporal dementia caused by C9orf72 repeat expansion.

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