Ss-siRNAs allele selectively inhibit ataxin-3 expression: Multiple mechanisms for an alternative gene silencing strategy

Jing Liu, Dongbo Yu, Yuichiro Aiba, Hannah Pendergraff, Eric E. Swayze, Walt F. Lima, Jiaxin Hu, Thazha P. Prakash, David R. Corey

Research output: Contribution to journalArticle

29 Scopus citations


Single-stranded silencing RNAs (ss-siRNAs) provide an alternative approach to gene silencing. sssiRNAs combine the simplicity and favorable biodistribution of antisense oligonucleotides with robust silencing through RNA interference (RNAi). Previous studies reported potent and allele-selective inhibition of human huntingtin expression by sssiRNAs that target the expanded CAG repeats within the mutant allele. Mutant ataxin-3, the genetic cause of Machado-Joseph Disease, also contains an expanded CAG repeat. We demonstrate here that ss-siRNAs are allele-selective inhibitors of ataxin-3 expression and then redesign ss-siRNAs to optimize their selectivity. We find that both RNAi-related and non-RNAi-related mechanisms affect gene expression by either blocking translation or affecting alternative splicing. These results have four broad implications: (i) ss-siRNAs will not always behave similarly to analogous RNA duplexes; (ii) the sequences surrounding CAG repeats affect allele-selectivity of anti-CAG oligonucleotides; (iii) ss-siRNAs can function through multiple mechanisms and; and (iv) it is possible to use chemical modification to optimize ss-siRNA properties and improve their potential for drug discovery.

Original languageEnglish (US)
Pages (from-to)9570-9583
Number of pages14
JournalNucleic Acids Research
Issue number20
Publication statusPublished - Nov 2013


ASJC Scopus subject areas

  • Genetics

Cite this