Trinucleotide repeat expansion (TRE)

Trinucleotide repeat expansions (TREs) are a class of genetic mutations characterized by an increase in the number of specific three-nucleotide sequences within a gene, leading to genomic instability and disease (Paulson, 2018). These expansions are dynamic, often lengthening across generations, and are responsible for over 40 neurological and neuromuscular disorders, including Huntington's disease, Myotonic dystrophy, and Friedreich's ataxia (NIH, 2023). The pathology typically arises from toxic gain-of-function at the RNA or protein level, or loss-of-function due to transcriptional silencing (Khorkova & Wahlestedt, 2017). Therapeutic strategies are diverse, ranging from antisense oligonucleotides (ASOs) like Tominersen that degrade toxic mRNA to gene-editing technologies like CRISPR/Cas9 designed to excise the expanded repeats (Tabrizi et al., 2022). Additionally, small molecules are being explored to target the secondary RNA structures formed by these repeats or to inhibit DNA repair proteins like MSH3 that facilitate repeat expansion (Nature Reviews Drug Discovery, 2023). Despite their potential, these therapies face significant challenges, including the need for precise allele-specific targeting and efficient delivery to the central nervous system (CNS).

Other names

Trinucleotide repeat expansionTriplet repeat expansionTNRETREMicrosatellite expansionDynamic mutation

Antisense-mediated RNA degradation, RNA interference (RNAi), CRISPR/Cas9-mediated gene excision, Small molecule binding to RNA hairpins, Splicing modulation, DNA mismatch repair (MMR) inhibition