Targeting Toxic Repeats

Abstract

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.

Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1

“… 6 Several repeat expansion disorders are gain-of-function diseases caused by either (1) toxic RNAs, which sequester RNA-binding proteins, (2) toxic protein products, such as the polyglutamine protein produced in Huntington’s disease (HD) and dipeptide-repeat-containing proteins in C9orf72 amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), or (3) a combination of both. 7 In many cases, blocking ASOs and gapmers can both be used to reduce the RNA or protein toxicity caused by the expanded repeat.…”

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

“…There is no cure for DM1 and treatment is currently limited to disease management [14]. When it comes to therapeutic approaches directed at the cause of disease, several strategies are being tested by different laboratories [15,16,17]. The main three classes of therapeutics are small molecules, antisense oligonucleotides and gene editing technology, including CRISPR/Cas.…”