CRM Seminar - Professor Sarah Tabrizi

Professor Sarah Tabrizi, Head of Department of Neurodegenerative Disease and Professor of Clinical Neurology & Neurogenetics at University College London

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.