High-throughput screen for genetic modifier inhibitors in Huntington's disease

Huntington’s disease (HD) is one of over 60 human diseases caused by repeat expansions in specific genes. Many of these diseases are characterised by progressive and devastating neurological and/or neurodegenerative pathology and, notably, none has a treatment that can alter the disease course. Therefore, there remains a clear unmet clinical need for urgent drug development in HD and related repeat expansion disorders. Excitingly, recent genetic discoveries of common pathogenic pathways have opened up new therapeutic avenues that we believe could ultimately lead to an effective treatment applicable to many of these diseases. HD is characterised by neurodegeneration in the brain, leading to loss of movement control, psychiatric symptoms, dementia and, ultimately, premature death. HD affects about 1 in 8,000 in the UK. It is a genetic, autosomal dominant condition that often devastates families as well as having an economic cost of >£260M per year in the UK alone. HD is caused by a single expanded repeat tract of at least 36 CAGs in the HTT gene. Longer repeat tracts are associated with earlier onset of disease symptoms and faster progression. However, there is much variation, some of which is heritable. Recent human genetic studies have identified a small number of genes associated with altered onset and/or progression of HD. This is important as it helps identify critical drivers of disease trajectory- and shows that disease course can be modified in people. These ‘modifier genes’ mostly have roles in DNA repair and subsequent work has shown that they alter the stability of the disease-causing CAG repeat in disease-relevant cells such as the medium spiny neurons of the striatum in the brain. Such ‘somatic expansion’ of the CAG repeat beyond its inherited length is now considered the key pathogenic driver in HD and other repeat expansion disorders. Importantly, by identifying genetic modifiers of disease onset and linking them to the pathogenic mechanism of somatic expansion, we have discovered novel drug targets that could be useful not just in HD, but in the broader family of repeat expansion disorders. In this project, we will combine our cutting-edge expertise in HD/repeat expansion disorder pathology and early-stage drug discovery to prosecute a novel drug target with very strong human genetic evidence that it is a disease modifier. We aim to discover and develop a small molecule inhibitor of this modifier protein that has a central role in driving somatic CAG repeat expansion in HD. We will use a high-throughput screen to identify small molecule inhibitors of a key protein activity before running a counter-screen to ensure appropriate specificity. Tool compounds will be developed and then assayed in our unique, bespoke, HD patient-derived induced pluripotent stem cell/neuronal model of somatic expansion. By the end of the project we aim to have identified a tool compound that shows efficacy in inhibiting the key cellular process of somatic expansion in a disease-relevant neuronal model system. If successful, future funding applications will focus on further optimisation and development of the inhibitors for pre-clinical in vivo evaluation and downstream pre-clinical candidate selection and clinical development. Given the lack of a disease-modifying therapy in HD, or any of the other repeat expansion disorders, progress towards an inhibitor of somatic expansion has the potential to have a high impact across many currently untreatable conditions.