CRM Seminar - Professor Sarah Tabrizi

Professor Sarah Tabrizi, Director, Huntington’s Disease Centre, and Joint-Head, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology

Talk Title: Huntington's Disease at an Inflection Point: New Genetics, New Mechanisms, New Therapeutics 

Abstract: Huntington's disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT). This talk will trace the arc from genetic cause to clinical disease to emerging therapeutics; reviewing the clinical features and trajectory of HD in humans before turning to the mechanistic and therapeutic advances now reshaping the field. HD pathogenesis is increasingly understood as a two-step process. The first step is a rate driver: somatic expansion of the CAG repeat in vulnerable neurons, modulated by a network of DNA repair proteins. The second step involves toxicity drivers, potentially exon 1a fragment proteins and N-terminal proteolytic fragments of full-length mutant HTT, with RAN translation and RNA toxicity as possible additional contributors. Downstream, this drives nuclear and cytosolic aggregation of HTT, epigenetic dysregulation, defects in axonal transport and synaptic function, and impairment of proteostasis, with early transcriptional dysregulation emerging as a key pathogenic marker. Much of the underlying molecular detail remains incompletely understood, and this two-step model may extend to repeat expansion diseases more broadly — a possibility I will briefly review. I will then discuss the diverse therapeutic modalities now in development, targeting huntingtin at the DNA, RNA, and protein level, including recent gene therapy results, and close with an overview of the current clinical development landscape and the challenges that remain in treating this complex genetic disease.

Bio: Sarah Tabrizi is Director of the UCL Huntington’s Disease (HD) Centre, Head of Department Neurodegenerative Disease at the UCL Queen Square Institute of Neurology, a Principal Investigator at the UK Dementia Research Institute, and Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. She graduated in Biochemistry with a First class degree, then studied Medicine at the University of Edinburgh where she was awarded the 1992 Leslie Gold Medal for the most distinguished medical graduate. Sarah undertook her PhD in biochemistry at UCL and then trained as an independent clinician scientist at UCL, establishing a large basic bench science and translational research team focussed on understanding mechanisms of disease, and finding disease modifying therapies for HD. She has led multiple first in human clinical trials including the first successful phase 1/2b trial of an antisense oligonucleotide (NEJM 2019) and currently serves on several SABs advising industry and government agencies on the development of potential gene targeting and nucleic acid therapies for HD. Sarah has over 420 peer-reviewed research publications. 

In 2014 she was elected as a Fellow of the UK Academy of Medical Sciences. In 2017 she received the seventh Leslie Gehry Brenner Prize for Innovation in Science awarded by the Hereditary Disease Foundation. In 2018 she received the Cotzias Award from the Spanish Society of Neurology, and in 2019 the Yahr Award at the World Congress for Neurology and the Alexander Morison Medal from the Royal College of Physicians of Edinburgh. In 2022, she received the Osler Medal from the Association of Physicians of Great Britain and Ireland, and the 2022 MRC Millennium Medal for her outstanding achievements in medical research. In 2023, she received the Arvid Carlsson award from Lund University for her research in Huntington’s disease mechanisms and therapeutics. In 2024, she was elected to the Fellowship of the Royal Society and to the US National Academy of Medicine for her research in HD. In 2025, she received the British Neuroscience Association’s Outstanding Contribution to Neuroscience Award. In 2026 Sarah was awarded a CBE in honour of her services to Huntington’s disease.