Targeting DNA repair for dementia treatments

Our DNA is the recipe that shapes a big part of how we’re built, how we work and who we are. It is therefore vital that it is well maintained by biological repair mechanisms that identify and correct damage to DNA molecules. As we age, however, these processes themselves can falter and there is growing evidence to suggest malfunctioning DNA repair mechanisms may be important in the development of diseases that cause dementia, and an exciting avenue for novel dementia therapeutics. 

To bring together expertise and identify strategies for translation in this emerging field, we formed the DNA repair theme in September 2020. Leading the collective are Group Leaders Prof Vincent Dion (UK DRI at Cardiff) and Dr Gabriel Balmus (UK DRI at Cambridge), who are working to develop ambitious research ideas, coordinate resource sharing and promote cross-centre collaborative schemes through regular, focused meetings and workshops. We spoke to Prof Dion and Dr Balmus to find out more about why DNA repair is an exciting avenue to explore in dementia, what activities are happening in the theme and future plans.

Vincent: “Our DNA is vulnerable to damage from a myriad of sources, including UV light, chemicals, and molecules naturally present in cells. DNA repair mechanisms are crucial to protect the integrity of the genome by identifying and correcting damage, but this capacity for repair is thought to decline as we age, leading to an accumulation of DNA damage. Effective DNA repair is vital for preventing cancers and several drugs already target these mechanisms. There is still much more to learn about DNA repair in neurons but we’re optimistic that there could be opportunities for developing treatments for the diseases that cause dementia too.”

Gabriel: “Literature from the last few years suggests that DNA repair genes are involved in several neurodegenerative conditions including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. Research into Huntington’s disease has received the greatest focus though and recent genome-wide association studies show genes associated with DNA repair can modify disease onset and severity. This is thought to be driven by somatic expansion of the already expanded CAG repeat region in the gene that causes Huntington’s disease, and therefore at the UK DRI we have an interest in understanding how somatic instability occurs. A major long-term goal is to find commonalities between neurodegenerative diseases outside the expanded repeat disorders.

Vincent: “We’re also very interested in other ways that DNA repair may impact neurodegeneration. For example, neuroinflammation has been shown to be a key characteristic of many brain diseases and we’d like to explore its interactions with DNA repair pathways.  

Vincent: “As with all potential mechanisms, we still need to evaluate whether malfunctioning DNA repair is a driver of disease or a consequence of neurodegeneration. This will of course have an impact on the stage of intervention and effectiveness of treatments.”

However, as mentioned, drugs affecting DNA repair have been developed for cancer treatment, and therefore we see great potential in repurposing or adapting these drugs for neurodegenerative diseases. The cancer field has even been using DNA repair function as a biomarker, which could be explored for brain diseases.”

Gabriel: “With regard to therapeutic opportunities, the field has begun by taking advantage of our solid understanding of repeat instability and we aim to develop treatments directed at reducing repeat expansion or inducing repeat contractions.

“One of the most promising lines of enquiry is focused on DNA mismatch repair (MMR). Knocking out some MMR components has been shown to reduce somatic expansion and improve outcomes in mouse models of Huntington’s. By identifying treatments to inhibit these MMR components, we may be able to prevent progression of the disease.

Vincent: “Our main goal is to catalyse discussions, collaborations and resource sharing to better understand how DNA repair contributes to neurodegeneration and find strategies to target these biological pathways with treatments. Among our initial areas of focus are Huntington’s disease and other repeat expansion disorders, but we welcome input from those working outside these conditions and fields of expertise such as inflammation.

We are fortunate to have a wealth of expertise across at the UK DRI and wider collaborative networks, bringing together basic scientists with leading clinical researchers like Professor Sarah Tabrizi from UK DRI at UCL. This puts us in a fantastic position to take advantage of translation opportunities and see discoveries through from bench to clinic.”

Gabriel: “In terms of activities, we hope to collate DNA repair assays and reagents already available in the network to facilitate cross-centre collaborations, funding bids, and interactions with industry. We already hold regular strategic meetings where we discuss our plans for the theme and develop ideas for collaborative research, which we then translate into proposals for funding from the UK DRI and external funders.”

Vincent: “We have a very proactive Early Career Researcher (ECR) steering committee led by Dr Georgina Menzies from UK DRI at Cardiff. The team organise ECR events such the 2-day virtual DNA Repair meeting that took place in the middle of February. The event included talks from keynote speakers, a workshop on peer reviewing, and shorter talks from ECRs in the theme. We also launched a pilot of the UK DRI mentoring scheme during the event.

What future activities do you have planned?

Gabriel: “We are looking to hold an international ‘DNA Repair in Neurodegeneration’ conference in 2022, which we hope will become a biennual event where we can discuss advancements in the field. We want to bring experts in DNA repair together with dementia researchers to introduce more researchers to this topic, and to learn from the cutting-edge research in both fields.”
 

For more information or to explore collaboration opportunities with any of the UK DRI Group Leaders, please contact UK DRI Director of Innovation and Business, Dr Kay Penicud.

Article published: 26 April 2021
Banner image - DNA Ligase: Tom Ellenberger, Washington University School of Medicine in St. Louis/Wikipedia