New study could pave the way for Huntington's disease therapies

The progressive neurodegenerative disorder affects about one in 10,000 people in the UK.

Researchers have identified a new mechanism that could stop the progression of Huntington’s disease in cells.

The scientists say the breakthrough study could lead to much-needed therapies for the genetic disease, which is rare and incurable.

Huntington’s disease is a progressive neurodegenerative disorder that affects about one in 10,000 people in the UK.

It is caused by the build-up 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.

Researchers at UCL and the University of Cambridge, as part of their research groups at the UK Dementia Research Institute, looked at 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.

The scientists found that FAN1 can block the accumulation of the DNA mismatch repair factors to stop repeat expansion, and therefore 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.”

They suggest medicines that could mimic or increase the power of FAN1 inhibition of mismatch repair would alter disease course.

The researchers are 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, said: “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.”

The study published in Cell Reports was funded by the CHDI Foundation and UK Dementia Research Institute.

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