Groundbreaking study could lead to much-needed therapies for Huntington’s disease

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 groundbreaking 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 disease, affecting around 1 in 10,000 people in the UK.

The disease is caused by the build-up of toxic repetitive expansions of three blocks of DNA called nucleotides (C, A, and G) in the huntingtin (HTT) gene and is often referred to as repeated expansion disorder. These CAG trinucleotide repeats are multiplied by misuse of a cellular machinery which generally promotes DNA repair called “mismatch repair”. This overuse in mismatch repair results in the onset and progression of Huntington’s disease.

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

Using human cells and techniques capable of reading repeated DNA expansions, the researchers found that FAN1 can block the build-up of DNA mismatch repair factors to stop repeated expansion, thereby attenuating the toxicity in cells derived from patients.

Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both from the Queen Square Institute of Neurology at UCL and the UK Dementia Research Institute at UCL, said: Still waiting to be discovered , which is good news for patients. “

Drugs which could mimic or potentiate (increase the potency of) the inhibition of FAN1 of mismatch repair would modify the course of the disease. The team is now working with biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these findings into therapies for a substantial number of patients in the UK and around the world.

Our next step is to determine the importance of this interaction in more physiological models and to examine whether it is therapeutically treatable. We are now working with key pharmaceutical partners to try to develop therapies that target this mechanism and may one day reach the clinic. “

Professor Sarah Tabrizi, Principal author, Ddirector, UCL Huntington’s Disease Center, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL

Joint lead author Dr Gabriel Balmus of the UK Dementia Research Institute at the University of Cambridge said: “There are currently over fifty disorders of the repeated expansion of CAG that are incurable. If viable, the field suggests that the resulting therapies could be applied not only to Huntington’s disease but to all other recurrent expansion disorders. “

Professor Steve Jackson, CSO and Acting 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 into new drugs for Huntington’s disease and potentially other DNA repeat expansion disorders as well. “

The study was funded by the CHDI Foundation and the UK Dementia Research Institute.