CHAPTER 7: Targeting Toxic Repeats

Repetitive sequences in the genome may become unstable above a certain length and elicit distinct pathological cascades. Prominent examples of diseases caused by these types of repeats are C9orf72-amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), Huntington's disease, myotonic dystrophy and several forms of spinocerebellar ataxia. These diseases share the presence of an expanded repeat, but differ in the sequence or in the mutated gene in which the repeat is located. Expanded CAG repeats, such as in Huntington's disease and most spinocerebellar ataxias, result in the synthesis of toxic polyglutamine-containing proteins. The CUG and GGGGCC repeats in myotonic dystrophy and C9orf72-ALS/FTD, respectively, form aberrant structures that sequester cellular factors and direct the production of toxic polymeric polypeptides via repeat-associated non-AUG translation. Despite the diversity in molecular mechanisms underlying these diseases, they have in common repetitive DNA and RNA segments that can serve as molecular targets for therapy. Here, we will discuss differences and similarities between repeat-expansion diseases, review the higher-order structures that can be formed by expanded repeats and provide an overview of how small molecules, antisense strategies and gene-editing strategies against toxic repeats have shaped a solid foundation for future therapy.