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

Research output: Contribution to journalArticle

172 Citations (Scopus)

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

Fingerprint

Huntington Disease
RNA Interference
Alleles
RNA
Nucleic Acids
Argonaute Proteins
Intraventricular Infusions
Antisense Oligonucleotides
Gene Silencing
Mutant Proteins
Nervous System Diseases
MicroRNAs
Small Interfering RNA
Brain
Genes
Pharmaceutical Preparations
Proteins

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., ... 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

Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. / Yu, Dongbo; Pendergraff, Hannah; Liu, Jing; Kordasiewicz, Holly B.; Cleveland, Don W.; Swayze, Eric E.; Lima, Walt F.; Crooke, Stanley T.; Prakash, Thazha P.; Corey, David R.

In: Cell, Vol. 150, No. 5, 31.08.2012, p. 895-908.

Research output: Contribution to journalArticle

Yu, D, Pendergraff, H, Liu, J, Kordasiewicz, HB, Cleveland, DW, Swayze, EE, Lima, WF, Crooke, ST, Prakash, TP & Corey, DR 2012, 'Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression', Cell, vol. 150, no. 5, pp. 895-908. https://doi.org/10.1016/j.cell.2012.08.002
Yu D, Pendergraff H, Liu J, Kordasiewicz HB, Cleveland DW, Swayze EE et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012 Aug 31;150(5):895-908. https://doi.org/10.1016/j.cell.2012.08.002
Yu, Dongbo ; Pendergraff, Hannah ; Liu, Jing ; Kordasiewicz, Holly B. ; Cleveland, Don W. ; Swayze, Eric E. ; Lima, Walt F. ; Crooke, Stanley T. ; Prakash, Thazha P. ; Corey, David R. / Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. In: Cell. 2012 ; Vol. 150, No. 5. pp. 895-908.
@article{2b0dec70d88c4809afb1b5d88f7588a1,
title = "Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression",
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.",
author = "Dongbo Yu and Hannah Pendergraff and Jing Liu and Kordasiewicz, {Holly B.} and Cleveland, {Don W.} and Swayze, {Eric E.} and Lima, {Walt F.} and Crooke, {Stanley T.} and Prakash, {Thazha P.} and Corey, {David R.}",
year = "2012",
month = "8",
day = "31",
doi = "10.1016/j.cell.2012.08.002",
language = "English (US)",
volume = "150",
pages = "895--908",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression

AU - Yu, Dongbo

AU - Pendergraff, Hannah

AU - Liu, Jing

AU - Kordasiewicz, Holly B.

AU - Cleveland, Don W.

AU - Swayze, Eric E.

AU - Lima, Walt F.

AU - Crooke, Stanley T.

AU - Prakash, Thazha P.

AU - Corey, David R.

PY - 2012/8/31

Y1 - 2012/8/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84865688581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865688581&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.08.002

DO - 10.1016/j.cell.2012.08.002

M3 - Article

C2 - 22939619

AN - SCOPUS:84865688581

VL - 150

SP - 895

EP - 908

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -