Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression

Dongbo Yu, Hannah Pendergraff, Jing Liu, Holly B. Kordasiewicz, Don W. Cleveland, Eric E. Swayze, Walt F. Lima, Stanley T. Crooke, Thazha P. Prakash, David R. Corey

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174 Scopus citations

Abstract

Mutant huntingtin (HTT) protein causes Huntington disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single-stranded antisense oligonucleotides with the efficiency of RNAi. Here, we describe RNAi by single-stranded siRNAs (ss-siRNAs). ss-siRNAs are potent (>100-fold more than unmodified RNA) and allele-selective (>30-fold) inhibitors of mutant HTT expression in cells derived from HD patients. Strategic placement of mismatched bases mimics micro-RNA recognition and optimizes discrimination between mutant and wild-type alleles. ss-siRNAs require Argonaute protein and function through the RNAi pathway. Intraventricular infusion of ss-siRNA produced selective silencing of the mutant HTT allele throughout the brain in a mouse HD model. These data demonstrate that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development.

Original languageEnglish (US)
Pages (from-to)895-908
Number of pages14
JournalCell
Volume150
Issue number5
DOIs
StatePublished - Aug 31 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yu, D., Pendergraff, H., Liu, J., Kordasiewicz, H. B., Cleveland, D. W., Swayze, E. E., Lima, W. F., Crooke, S. T., Prakash, T. P., & Corey, D. R. (2012). Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell, 150(5), 895-908. https://doi.org/10.1016/j.cell.2012.08.002