Genetic discoveries are opening up new therapeutic options for Huntington’s disease, British researchers have reported.
Huntington’s disease is a neurodegenerative condition which is caused by build up of three DNA blocks called nucleotides C, A and G in the huntingtin gene.
New genome-wide studies have identified genetic variations that affect the age of disease onset. These are found on the FAN1 gene, which is found on chromosome 15 and controls a DNA repair enzyme.
Dr Rob Goold and colleagues at University College London, UK, looked at the FAN1 in tests of patient-derived stem cells and found that increased expression is significantly linked to a delayed age of onset and slower disease progression.
This "suggests FAN1 is protective in the context of an expanded Huntington’s disease CAG repeat," they write in yesterday’s Cell Reports.
They add: "FAN1 knockdown increases CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of Huntington’s disease act to alter disease progression.
"This provides new avenues for therapeutic interventions in Huntington’s disease and potentially other triplet repeat disorders."
Dr Goold 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.”
Co-author Professor Sarah Tabrizi added: “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.”
Goold, R. et al. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease. Cell Reports 31 August 2021; doi: 10.1016/j.celrep.2021.109649
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