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EHDN 2022 | Somatic expansion as a novel therapeutic approach for Huntington’s disease

The role of somatic instability as a driver of Huntington’s disease (HD) onset and progression has been a breakthrough in recent years. The expanded CAG repeat in the mutated huntingtin (mHTT) gene is inherently unstable and tends to undergo progressive length increases over time. Notably, these expansions differ by cell and tissue type and are most prominent in the striatum and cortex, areas which are most profoundly affected early in HD. It has been shown that as well as inherited repeat length, the degree of somatic expansion in the brain influences age of onset. More recently, genome wide associated studies have identified single nucleotide polymorphisms in DNA repair genes (including FAN1, MSH3, MLH1, PMS2, and LIG1) as modifiers of HD onset and severity, thought to be exerting their effects through modulation of the rate of somatic expansion. These observations have piqued interest in how the disease could be treated by suppressing somatic expansion. Michael Hayden, MB, ChB, PhD, FRCP, FRSC, The University of British Columbia, Vancouver, Canada, & Prilenia, CEO, comments on the potential of somatic expansion as a therapeutic target, including challenges surrounding delivery and biomarkers that must be overcome. Prof. Hayden notes the promise of oral agents as a way to achieve target engagement throughout the brain, rather than selective delivery systems. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.

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