Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Inês Lopes Cardoso

doi:10.21926/obm.genet.1803025

Abstract

Dynamic mutations involve expansion of the number of repeat units consisting of three or more nucleotides in tandem (i.e., adjacent to one another), present in a gene or in its neighborhood. Depending on expansion size, unaffected individuals can be carriers of a pre-mutation. Instability of triplet repeats can lead to gradual expansion through generations and accumulation of a certain number of repeats can lead to the consequent development of disease. The increase in the number of triplet repeats from one generation to the next, resulting from repeat instability, leads to the reduction in the age of disease onset and worsening of symptoms in affected individuals in successive generations. There is still no treatment for this type of diseases, however, several strategies are under study. This work describes treatment approaches for triplet repeat expansion diseases that have been developed during the last years, having as target DNA or RNA molecules. Some of these strategies might be used in the future as gene therapy of trinucleotide repeat disorders.

Highlights

All eukaryotic and prokaryotic genomes contain a certain number of repetitive sequences that can vary in length and repetitive levels similar to long repeats and satellite DNA [1,2,3,4]
Examples of this type of disease include myotonic dystrophy (DM) Huntington disease (HD), fragile X syndrome, and many others resulting from the accumulation of triplet repeats (CTG-CAG, CGG-CCG or GAA-TTC) in corresponding genes [9, 10]
RNA-targeting has been developed using three main strategies directed against triplet RNA repeats: RNA interference (RNAi), antisense oligonucleotides (ASOs) or the use of splicing inhibitors

Summary

Introduction

All eukaryotic and prokaryotic genomes contain a certain number of repetitive sequences that can vary in length and repetitive levels similar to long repeats and satellite DNA [1,2,3,4]. Trinucleotide repeat expansions have been identified as the cause of approximately 20 neurologic and neuromuscular diseases, the mechanisms underlying their development remain to be elucidated [5, 9]. Examples of this type of disease include myotonic dystrophy (DM) Huntington disease (HD), fragile X syndrome, and many others resulting from the accumulation of triplet repeats (CTG-CAG, CGG-CCG or GAA-TTC) in corresponding genes [9, 10]. We discuss the most recently studied treatment approaches directed against nucleic acids, some of which have potential applications in future gene therapy of trinucleotide repeat expansion disorders

Materials and Methods

Experimental Therapies Directed Against Triplet Repeats

RNA-Targeting Strategies

DNA Targeting Strategies

Findings

Conclusion