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New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease

Date:
August 31, 2021
Source:
University College London
Summary:
A new mechanism that stops the progression of Huntington's disease in cells has been identified.
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A new mechanism that stops the progression of Huntington's disease in cells has been identified by scientists at UCL and the University of Cambridge, as part of their research groups at the UK Dementia Research Institute.

Researchers say the breakthrough study, published in Cell Reports, could lead to much needed therapies for the rare genetic disease, which is currently incurable.

Huntington's disease is a progressive and devastating neurodegenerative disorder, that affects about 1 in 10,000 people in the UK.

The disease is caused by the accumulation of toxic repetitive expansions of three DNA blocks called nucleotides (C, A and G) in the huntingtin (HTT) gene and is often termed a repeat expansion disorder. These CAG tri-nucleotide repeats are expanding by misuse of a cellular machinery that usually promotes DNA repair called 'mismatch repair'. This overuse in mismatch repair drives Huntington's disease onset and progression.

In this study researchers investigated the role of FAN1 -- a DNA repair protein, that has been identified as a modifier of Huntington's disease in several genetic studies; however, the mechanism affecting disease onset has remained elusive.

Using human cells and techniques that can read DNA repeat expansions, the researchers found that FAN1 can block the accumulation of the DNA mismatch repair factors to stop repeat expansion thus alleviating 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 potentiate (increase the power of) FAN1 inhibition of mismatch repair would alter disease course. The team is now working with the biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these discoveries into therapies for substantial numbers of patients in the UK and worldwide.

Senior author of the study, Professor Sarah Tabrizi, director of the UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, stated: "Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable. We are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic."

Joint senior author, Dr Gabriel Balmus from the UK Dementia Research Institute at the University of Cambridge, said: "There are currently more than fifty 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 Dementia Research Institute.


Story Source:

Materials provided by University College London. Note: Content may be edited for style and length.


Journal Reference:

  1. Robert Goold, Joseph Hamilton, Thomas Menneteau, Michael Flower, Emma L. Bunting, Sarah G. Aldous, Antonio Porro, José R. Vicente, Nicholas D. Allen, Hilary Wilkinson, Gillian P. Bates, Alessandro A. Sartori, Konstantinos Thalassinos, Gabriel Balmus, Sarah J. Tabrizi. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease. Cell Reports, 2021; 36 (9): 109649 DOI: 10.1016/j.celrep.2021.109649

Cite This Page:

University College London. "New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease." ScienceDaily. ScienceDaily, 31 August 2021. <www.sciencedaily.com/releases/2021/08/210831112227.htm>.
University College London. (2021, August 31). New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2021/08/210831112227.htm
University College London. "New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease." ScienceDaily. www.sciencedaily.com/releases/2021/08/210831112227.htm (accessed March 28, 2024).

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