Meet the Investigator

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Sarah Tabrizi, MBChB, PhD
Sarah Tabrizi, MBChB, PhD

VITAL SIGNS

NAME: Sarah Tabrizi

CURRENT POSITION: Professor of Clinical Neurology at University College London

EDUCATION: PhD Biochemistry University College London, MBChB University of Edinburgh

CURRENT HD ACTIVITIES: Dr. Tabrizi is leading efforts in translational medicine. She is lead investigator of the TRACK-HD study that investigates the neurobiology of premanifest and early onset HD and has already been successful in identifying biomarkers that can be used to track the progression of neurodegeneration from its onset in HD patients. She is also researching immunobiology in HD, and cellular mechanisms of protein misfolding diseases.

HOBBIES: Spending time with family, reading, and running.

LAST BOOK READ: Herzog by Saul Bellow. It was great but heavy going!

Dr. Tabrizi established her own consulting clinic and specialist HD clinic in 2003. Since then, she has published more than 120 peer-reviewed articles, which have appeared in Molecular Cell, Lancet Neurology, Nature Communications, Journal of Experimental Medicine, EMBO Journal and PNAS. In addition to her ongoing projects in HD immunobiology, protein misfolding, and the TRACK-HD study, she serves on executive panels for the UK HD association, the European HD Network and NINDS. Dr. Tabrizi sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss her HD research and hopes for the future of HD. Excerpts from the discussion are below.

INSIGHTS: What drew you to Huntington disease?

TABRIZI: My PhD supervisor Tony Schapira took me to a nursing home just outside London called Stagenhoe, where there were many patients with advanced Huntington disease. I was struck by the patients and how warm they were, how interested they were in the research. Then I met Gill Bates who had just published about her HD mouse. I followed up with the work Gill had done and also worked with her during my PhD. My PhD work cemented my interest in the disease. Once you start working in Huntington disease you get hooked.

INSIGHTS: You presented that a number of different biological markers that you’re helping develop track with HD. Can you tell us which of these biomarkers you view as the most promising?

TABRIZI: The markers that I’ve been most impressed with are the structural imaging markers –caudate volume, striatal volume, and whole brain atrophy. These are the markers that I think are the most promising and the most robust at this stage. However, a number of cognitive and quantitative motor markers are also important. We are developing these markers with our TRACK-HD team. The interesting part about the imaging is that we need to understand more about what these structural changes mean biologically. We need to understand what the pathological substrate is and the functional relevance of these imaging changes. That’s something through our ongoing work we’re seeking to do – to look at neural compensatory networks and functional plasticity.

INSIGHTS: You talked a little bit about your initial skepticism of structural imaging and how that’s been converted.

TABRIZI: My initial skepticism was that whether imaging would demonstrate convincing change, whether it would be robust enough, and whether you would be able to remove inter-scan variability to get good scan quality. Now I understand a great deal more about how the technologies. We have advanced ways of studying the brain, particularly with 3T MRI; we can very accurately and carefully map regions of the brain with very high sensitivity and low measurement error. Imaging gives us insight into regional changes. I’ve become converted in that imaging does appear to correlate very closely to functional and cognitive decline.

INSIGHTS: At the conference you also identified classes of experimental compounds that hold promise for Huntington disease. Can you discuss which of these you think holds the most promise?

TABRIZI: I wanted to give an overview of the compounds that were potentially neuroprotective or disease-modifying that would be going into clinical trials in the next 24 to 36 months. Phosphodiesterase inhibitors – phosphodiesterase 10 inhibitors, for example – are promising in pre-clinical data and have the potential to enhance synaptic function. Other compounds currently at or near clinic that have great potential are the KMO inhibitors that target peripheral immune cells. Also promising are those that use approaches such as ASOs and RNAi and aim to lower mutant huntingtin or enhance mutant Huntington clearance and/or correct gene transcriptional dysregulation, such as the SIRT1 inhibitor (Siena BioTech). In pre-clinical targets, the HDAC4 inhibitors are potentially exciting.

INSIGHTS: You mentioned phosphodiesterase 10 inhibitors had promising pre-clinical data. Can you tell us about that?

TABRIZI: There are two published recent papers in HD mouse models. In one, they use phosphodiesterase 10 inhibition treatment in primary striatal cultures, while in the other they have partly corrected synaptic dysfunction and transcriptional dysregulation. This is promising in that cAMP/cGMP downstream signaling has multiple beneficial effects on synaptic function and gene regulation.

INSIGHTS: How will those beneficial effects on synaptic function lessen the burden of Huntington disease?

TABRIZI: Huntington disease causes early synaptic functional defects and loss of the cortico striatal neural circuitry, as shown in numerous mouse model studies. Synaptic function is essential for memory, learning, and overall brain function, and very early neuronal loss and synaptic dysfunction occurs in Huntington disease. We know from TRACK-HD data that neuronal loss is also very likely to occur early in HD gene carriers. This is potentially reversible. If we can somehow promote synaptic function and promote synaptic plasticity, we can allow the brain to compensate for ongoing pathogenic effects of mutant huntingtin.

INSIGHTS: In the next few years what are the most promising avenues of research that we can expect to see coming out of the Tabrizi lab?

TABRIZI: I have a number of projects that are ongoing. I’m working on basic science and protein misfolding cell biology, particularly using prion cell biology as a model for protein misfolding biology. We’re looking at trying to understand how the misfolded prion proteins move around and use that as a model to take it forward to look at for example, mutant huntingtin trafficking. We’re also developing a number of human ex-vivo cell culture models to try and look at HD in a cell culture dish, as well as starting projects in which we probe the function of wild-type in peripheral human HD cells. On the more translational side, I have a big program looking at the role of the immune system and immune biology in modifying Huntington disease, while also investigating how wild-type and mutant huntingtin levels may vary between patients, how they may correlate with each other, and how they may link to disease progression. Finally, Track-On-HD is a new study aiming to explore neural compensatory networks and functional plasticity in the premanifest stage of Huntington disease. It’s essential to understand functional plasticity moving forward, especially in terms of future trials for pre-manifest individuals. Despite striking brain changes over time, our subjects are able to function at a high level. There must be remodeling and functional plasticity of synapses for this to occur. We’re using a number of novel methods to look and see if we can identify these neural compensatory networks. Clearly this will also give functional relevance to structural imaging. These are the main projects over the next two years and hopefully we’ll get some exciting and important data.

INSIGHTS: Thank you very much and your final thoughts?

TABRIZI: The meeting here in Melbourne has been really exciting. There’s a great feeling of positivity. The families that are here feel the progress has been made, and that we’re working together avidly to try and find potential treatment for Huntington disease. It is a great community.

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