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Mechanism preventing Huntington's disease progression could lead to new therapies

6 September 2021
Appeared in BioNews 1111

A mechanism for boosting the activity of a DNA repair protein involved in Huntington's disease has been discovered, creating a potential treatment avenue.

Researchers from University College London (UCL) and the University of Cambridge have investigated the role of FAN1, a DNA repair protein, in Huntington's disease progression. Previous studies have identified FAN1 as a modifier of Huntington's disease, however, the mechanism has remained unknown - until now.

'It's an exciting time in the Huntington's disease field as there is a huge amount of work being conducted regarding DNA repair mechanisms,' co-lead author from UCL, and BioNews volunteer writer, Joseph Hamilton told BioNews. 'Although we have a grounding of how these genes are involved in somatic expansion, our work highlights that there is so much more waiting to be uncovered.'

Huntington's disease occurs when a genetic mutation causes accumulation of repetitive strings of a 'CAG' sequence in the huntingtin gene, causing a build-up of toxic amounts of this short DNA sequence leading to Huntington's disease onset and progression. For this reason, this untreatable disease, affecting one in 10,000 people in the UK, is often referred to as a repeat expansion disorder.

The researchers, who have published their results in Cell Reports, used human cells as well as techniques that can read DNA repeats, to highlight FAN1 mechanisms in Huntington's disease. They discovered that the FAN1 protein blocked accumulation of DNA mismatch repair factors, halting CAG expansion and reducing cellular toxicity.

Additionally, the authors state that FAN1's activity potentially promotes the accurate repair of erroneous CAG repeats, which alleviates the toxicity of this DNA sequence in cells. The authors explain that medicines mimicking FAN1 to block the mismatch repair may alter the disease course, which could translate into therapies.

Dr Gabriel Balmus, joint lead author from 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.'

The team are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic. Professor Sarah Tabrizi, director of the UCL Huntington's Disease Centre, explained that the 'next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable.'

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