Our research
Research within the HD Centre in Wales covers everything from basic cell biology to big data studies of patients to the pioneering development of new treatments. Our research is grouped into 5 themes:
1.
Cellular and molecular mechanisms of HD
Led by Dr Vincent Dion
We know that Huntington's disease is caused by a CAG repeat expansion in the HTT gene and results in the degeneration of specific neurons in the brain. However, we do not fully understand the pathological steps that link the CAG repeat expansion to neuronal cell death. We need to understand these steps so that we can design new ways of blocking them, ultimately resulting in therapeutics that can protect neurons from degeneration in HD.
In HDCiW we have researchers exploring how the CAG repeat expansion affects RNA biology in cells (Langley group), how the expansion is involved in DNA repair processes (Dion group), and how long repeats lead to aggregation and neurodegeneration (Smith group). We have researchers modelling how protein structures of HTT and disease modifiers might impact disease (Menzies group) and others exploring the thresholds at which a long CAG repeat becomes toxic to neurons (Massey group).
2.
Genetic modifiers of HD
Led by Dr Tom Massey
HD is caused by a single genetic mutation, an expanded CAG repeat tract, in the HTT gene. This is sufficient to cause HD, but there is massive variation in the age at which symptoms start and how the disease progresses. Thanks to groundbreaking human genetic studies to which HDCiW researchers have been integral, we now know that other genes can have a big impact on disease progression. These ‘genetic modifiers’ can tell us about the drivers of pathology in HD, but, more importantly, can identify new drug targets.
In the HDCiW we have researchers working on human genetic modifier identification (Holmans group) as well as others figuring out how modifiers impact HD by using stem cell models (Massey group) and Drosophila (fruit fly) models (Smith group, Taylor group).
3.
Brain networks and their involvement in HD
Led by Dr Claudia Metzler-Baddeley
Huntington’s disease (HD) disrupts communication within and between key brain networks, particularly the cortico-striatal circuit, which is essential for motor control and decision-making. Even before the clinical onset of motor symptoms, shrinkage of the caudate and putamen in the basal ganglia—likely due to the loss of medium spiny neurons (MSNs)—and widespread degeneration of white matter connections between brain regions can be observed. As the disease progresses, these disruptions extend beyond the basal ganglia to adjacent regions and cortical networks. Alterations in brain network structure and function have been closely linked to clinical symptoms and genetic burden. Research groups within the HDCIW (McLauchlan group, Erichsen group and Lelos group) are working to better understand the nature of brain network changes in HD. Some of this work utilises the state-of-the-art non-invasive imaging available at Cardiff University Brain Research Imaging Centre (CUBRIC) (Metzler-Baddeley group).
4.
Development of new therapies and treatments in HD
Led by Professor Anne Rosser
The genetic mutation that drives HD causes neuropathological changes in the brain, including early degeneration of the medium spiny neurons in the striatum, followed by more global brain atrophy. HD is currently untreatable, but the development of therapeutics to slow or stop the progression of the disease are at the forefront of our activities. To achieve this, we work with cell and animal models of HD to test new therapeutic approaches, determining the extent to which they are efficacious and considering closely their safety profiles. Working towards this goal, we have characterised several mouse and rat models of HD to determine the extent to which they replicate the motor, cognitive, neuropsychiatric phenotypes that emerge in HD, as well as exploring the molecular and cellular pathologies that manifest. Using these models, researchers within the HDCiW are testing pharmacological treatments (Lelos lab, Rosser lab, Medicines Discovery Institute), such as GABA modulators. A novel stem cell therapy to replace degenerated medium spiny neurons is in development and working towards safety and toxicity testing (Rosser and Lelos labs). A novel gene therapy, capable of reducing the genetic expansion key to HD, is in development (Dion lab). This work is occurring in close conjunction with neurosurgical academics (Gray lab), who are developing optimised methods to administer advanced therapeutics, such as cell and gene therapies. In addition, physiological approaches to improving disease progression with movement are being studied (Metzler-Badley lab) and patient perceptions of potential treatments are considered (Drew lab).
5.
Impact of HD on patients
Led by Dr Cheney Drew
Living with HD, both as someone who has had a genetic diagnosis or for those living with, or close to someone with a genetic diagnosis of HD, can generate many different challenges. Theses challenges occur in lots of different ways, which can have an overall impact on the quality of life for people living with HD and those that love and support them.
Whilst researchers worldwide work to look for new treatments that can slow down or stop the progression of HD, it is important that we explore ways that people can live well with HD. The research we do in this area is wide ranging and includes; looking at how exercise, physical therapy and a healthy lifestyle contributes to the impacts of living with HD through to understanding the needs and support required by people living with HD for taking part in research or for specific life decision such as family planning.
A really important part of this work involves listening to what people in the HD community have to say about their lives, what they need and what they want to see in research. By involving people with living with HD in the research we do, we can make sure that the research is relevant to and for the HD community.