Speakers
Session 2: Delivering in the Clinic
Huntington's disease (HD) is an inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT). The disease has a complex pathogenesis which involves somatic expansion of the CAG repeat in vulnerable neurons leading to the production of toxic protein species. This process results in significant downstream pathology, including: nuclear and cytosolic aggregation of HTT, epigenetic changes, defects in axonal transport and synaptic function and impairment of proteostasis. Early transcriptional dysregulation is a key pathogenic marker. However, the underlying molecular mechanisms of all these components are still not yet fully understood.
HD is now thought of as having a two-step pathogenesis – the rate driver (somatic expansion of the repeat), which is modified by a number of DNA repair proteins. Then step 2, toxicity drivers, potentially: exon 1a fragment proteins and N-terminal proteolytic fragments from full length mutant HTT. However, other processes involving possible RAN translation, and RNA toxicity may also be involved.
My talk will give an overview of HD clinical features, will cover the disease's pathogenesis and trajectory in humans, looking at the new insights within the mechanistic and therapeutic landscapes, with agents targeting huntingtin DNA, RNA and protein. I will also discuss in detail the diverse therapeutic modalities being tested and give an overview of the current state of clinical development including the future challenges we face treating this complex genetic disease.
Professor Sarah Tabrizi is a clinician-scientist internationally recognised for her pioneering research into Huntington’s disease and neurodegeneration. She is the Director of the UCL Huntington’s Disease Centre and Joint Head of the Department of Neurodegenerative Disease at UCL Queen Square Institute of Neurology. Her work combines basic cellular research with translational approaches to develop effective, disease-modifying therapies.
Professor Tabrizi has published over 300 peer-reviewed papers and serves on multiple expert panels, including the UK HD Association and the European HD Network. Her contributions to neuroscience have been recognised with numerous awards, such as the Leslie Gehry Brenner Prize for Innovation in Science and the Royal Society Fellowship.