Allele-selective inhibition of trinucleotide repeat genes

Abstract

Expanded trinucleotide repeats cause Huntington's disease (HD) and many other neurodegenerative disorders. There are no cures for these devastating illnesses and treatments are urgently needed. Each trinucleotide repeat disorder is the result of the mutation of just one gene, and agents that block expression of the mutant gene offer a promising option for treatment. Therapies that block expression of both mutant and wild-type alleles can have adverse effects, challenging researchers to develop strategies to lower levels of mutant protein while leaving adequate wild-type protein levels. Here, we review approaches that use synthetic nucleic acids to inhibit expression of trinucleotide repeat genes.

FIGURE 1

Mechanism of allele-selective inhibition. (a) Hairpin structure of CAG repeats. (b) Nonallele-selective inhibition of gene expression by small interfering (si) or short hairpin (sh) RNA. (c) Targeting single nucleotide polymorphisms (SNPs) with siRNA and/or shRNA. (d) Targeting expanded trinucleotide repeats with antisense oligonucleotides (ASOs). (e) Targeting expanded CUG repeats in dystrophia myotonica-protein kinase (DMPK) mRNA. (f) Targeting expanded trinucleotide repeats with mismatch-containing RNA. Abbreviations: AGO2, Argonaute 2; MBNL1, muscleblind-like protein 1; UTR, untranslated region.

FIGURE 2

Chemical structures of unmodified or modified nucleic acids used for antisense oligonucleotides (ASOs) and/or double-stranded (ds)RNAs targeting trinucleotide repeat genes.