Aurintricarboxylic Acid Decreases RNA Toxicity in a C. elegans Model of Repeat Expansions

Abstract

Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disease phenotypes. RNA toxicity is the hallmark of multiple expansion repeat disorders, including myotonic dystrophy type 1 (DM1). To date, there are no available disease-modifying therapies for DM1. Our aim was to use drug repositioning to ameliorate the phenotype of affected individuals in a nematode model of DM1. As the RNA interference pathway plays a key role in mediating RNA toxicity, we investigated the effect of aurintricarboxylic acid. We demonstrated that by perturbing the RNA interference machinery using aurintricarboxylic acid, we could annihilate the RNA toxicity and ameliorate the phenotype. As our approach targets a universal disease mechanism, it is potentially relevant for more expansion repeat disorders.

Transcriptome changes in DM1 patients’ tissues are governed by the RNA interference pathway

“…In previous work in C. elegans, we demonstrated that repeatderived siRNAs can target transcripts bearing endogenous CUG/ CAG repeats and induce disease symptoms through the RNAi machinery (Qawasmi et al, 2019;Braun et al, 2021;Braun et al, 2022). Knockdown of key components of the RNAi pathway resulted in the rescue of the disease phenotype.…”