A new cellular discovery could pave the way for new treatment options for Huntington’s disease, researchers say.
Scientists from the University of Cambridge and University College London (UCL), as part of their research groups at the UK Dementia Research Institute, have identified a key mechanism in cells that stops the progression of Huntington’s disease. This discovery, the researchers say, could lead to new therapies for the disease, which is currently incurable.
The study has been published in Cell Reports.
Huntington’s disease is a rare, inherited, and progressive neurodegenerative disease that currently affects around one in 10,000 people in the UK. The disease can have a significant impact on a person’s functional abilities and often results in movement, cognitive, and psychiatric disorders.
Huntington’s 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 referred to as 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 the study, researchers set out to explore the role of FAN1 – a DNA repair protein that has been identified as a modifier of Huntington’s disease in several genetic studies. Until now, 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. As a result, this alleviates toxicity in cells derived from patients.
Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both from 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.”
From the findings, the researchers determined that medicines that could mimic or potentiate (amplify the power of) FAN1 inhibition of mismatch repair would alter the course of the disease. The team is now working with biotechnology company Adrestia Therapeutics to use these new discoveries to develop therapies for 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 to develop therapies that target this mechanism and might one day reach the clinic.”
Therapies for various disorders
Joint senior author Dr Gabriel Balmus, from the UK Dementia Research Institute 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 Dementia Research Institute.