Poster 16: Genetic Approach to Huntington's Disease Therapeutics

Abstract

Background Unlike other neurodegenerative disorders, Huntington's disease, with its motor, behavioral, and cognitive deficits and early loss of neurons in the striatum, has a single cause: expanded versions of a polymorphic CAG repeat in the HTT gene (previously HD) of ≥35 units. This uniform starting point permits the development of therapeutics based solely upon the features of the HTT CAG repeat. Methods, Results, and Discussion We are applying global methods, such as genome-wide gene expression levels, to discover dominant and CAG length-dependent genes and pathways, using cells and tissues bearing the full-range of HTT CAG allele sizes. These phenotypes can potentially point to small molecule or gene modifiers and can be converted into cell-, pathway- or gene-based assays suitable for high-throughput screens to find modifiers of HTT CAG size-dependent effects in models and humans. This genetic approach to therapeutic target discovery has demonstrated that the HTT CAG repeat is a functional polymorphism that, over the non-HD and the HD ranges, affects energy, RNA metabolism, and the cytoskeleton. These HTT CAG size-dependent signatures provide an unbiased read-out for assays with which to find compounds or genes that may slow or halt the earliest phase of the HD disease process.