Huntington’s disease progression stopped in cell study by University of Cambridge and UCL researchers


Exciting progress has been made in the lab in the fight against Huntington’s disease.

Scientists at the University of Cambridge and UCL have identified a mechanism that stops its progression in cells.

They are now working with Babraham Research Campus-based biotech start-up Adrestia Therapeutics to translate the discovery into therapies.

Huntington’s is a devastating and currently incurable neurodegenerative disorder that affects about 1 in 10,000 people in the UK.

It is caused by the accumulation of toxic repetitive expansions of three DNA blocks, or nucleotides (C, A and G), in the huntingtin (HTT) gene. The disease is often termed a repeat expansion disorder.

In Huntington’s, cellular machinery that usually promotes a DNA repair process called ‘mismatch repair’ is overused, driving these CAG tri-nucleotide repeats and leading to the onset and progression of disease.

The researchers, working as part of Cambridge and UCL’s involvement in the UK Dementia Research Institute (DRI), investigated the role of a DNA repair protein called FAN1.

This has been identified as a modifier of Huntington’s disease in several genetic studies, although the mechanism affecting the onset of disease has remained elusive.

Using human cells and techniques that can read DNA repeat expansions, they found FAN1 can block the accumulation of the DNA mismatch repair factors. It was found to stop repeat expansion and alleviate toxicity in cells derived from patients.

Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, said: “Evidence for DNA repair genes modifying Huntington's disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.”

Medicines that could mimic or increase the power of FAN1 inhibition of mismatch repair could change the course of the disease.

Senior author of the study, Prof Sarah Tabrizi, director of the UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and UK DRI at UCL, said: “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable.”

Dr Gabriel Balmus, a joint senior author of the paper published in Cell Reports, from the UK DRI at the University of Cambridge, said: “There are currently more than 50 CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington's disease but to all the other repeat expansion disorders.”

Professor Steve Jackson, CSO and interim CEO of Adrestia, said: “My colleagues and I are delighted to be working with Professor Tabrizi, Dr Balmus and the UK Dementia Research Institute to seek ways to translate their exciting science towards new medicines for Huntington's disease and potentially also other DNA-repeat expansion disorders.”

The study was funded by the CHDI Foundation and UK DRI.

Published on: 08.09.21

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